KR19980701836A - 2-aminoindane as Selective Dopamine Di3 Ligand - Google Patents

2-aminoindane as Selective Dopamine Di3 Ligand Download PDF

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KR19980701836A
KR19980701836A KR1019970705233A KR19970705233A KR19980701836A KR 19980701836 A KR19980701836 A KR 19980701836A KR 1019970705233 A KR1019970705233 A KR 1019970705233A KR 19970705233 A KR19970705233 A KR 19970705233A KR 19980701836 A KR19980701836 A KR 19980701836A
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아터 지 로메로
제프리 에이 레이비
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웰츠 로렌스 티
파마시아 앤드 업존 캄파니
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Abstract

본 발명은 도파민 D3 수용체 활성과 연관된 중추 신경계 질환의 치료에 적합한 하기 화학식 (I)의 화합물 및 약학적으로 허용가능한 염에 관한 것이다:The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts which are suitable for the treatment of central nervous system diseases associated with dopamine D3 receptor activity:

화학식 IFormula I

상기 식에서,Where

R1및 R2는 독립적으로 H, C1-C8알킬 또는 C1-C8알킬아릴이고;R 1 and R 2 are independently H, C 1 -C 8 alkyl or C 1 -C 8 alkylaryl;

X는 CH2R3또는 NHSO2R4이고;X is CH 2 R 3 or NHSO 2 R 4 ;

Y는 수소, CH2R3, NHSO2R4, CONR1R2, SO2NR1R2, SO2CH3, 할로겐, OSO2CF3, SCH3또는 OCH3이고;Y is hydrogen, CH 2 R 3 , NHSO 2 R 4 , CONR 1 R 2 , SO 2 NR 1 R 2 , SO 2 CH 3 , halogen, OSO 2 CF 3 , SCH 3 or OCH 3 ;

R3는 NHSO2R4, SO2R4, CONR1R2또는 아릴이고; 및R 3 is NHSO 2 R 4 , SO 2 R 4 , CONR 1 R 2 or aryl; And

R4는 NR1R2, C1-C8알킬, 아릴 또는 C1-C8알킬아릴이다.R 4 is NR 1 R 2 , C 1 -C 8 alkyl, aryl or C 1 -C 8 alkylaryl.

Description

선택적인 도파민 디3 리간드로서의 2-아미노인단2-aminoindane as Selective Dopamine Di3 Ligand

본 발명은 실험실내에서 도파민 D3 수용체에 선택적으로 결합하는 2-아미노인단 유사체에 관한 것이다. 도파민 D3 수용체는 최근 소콜로프(Sokoloff) 등의 문헌[Nature, 347, 146(1990)]에 의해 무성생식되었다. 이러한 수용체 하부유형(subtype)이 정신병 치료약의 작용에 중요하다고 가정되었다. 흥미롭게도, 이 수용체는 감정 및 인지 기능과 관련된 뇌 영역에 상당히 풍부하게 존재한다.The present invention relates to 2-aminoindane analogs which selectively bind to the dopamine D3 receptor in the laboratory. Dopamine D3 receptors have recently been asexually reproduced by Sokoloff et al., Nature, 347, 146 (1990). It was assumed that this receptor subtype is important for the action of antipsychotics. Interestingly, these receptors are fairly abundant in the brain regions involved in emotional and cognitive functions.

이러한 개념을 갖는 화합물은 CNS 질환(예, 정신분열증, 조병, 우울증, 노인성 질환, 약물 남용 및 약물 중독, 파킨슨병, 불안 질환, 수면 질환, 일주기 질환 및 치매)을 치료하는데 유용할 수 있다.Compounds having this concept may be useful for treating CNS diseases (eg, schizophrenia, mania, depression, senile disease, drug abuse and drug addiction, Parkinson's disease, anxiety disease, sleep disease, circadian disease and dementia).

관련정보 개시 문헌: Related Information

아네릭 에스. 피.(Arneric S. P.) 등의 문헌[Neuropharmacol.,21, 885(1982)]은 다른 도파민 작용물질과 비교되는 인단 유사체를 개시한다. 5,6 치환을 갖는 화합물은 이러한 모델의 음식 섭취에서 불활성인 것으로 밝혀졌다.Aneric S. Arneric SP, et al., Neuropharmacol., 21 , 885 (1982), discloses indan analogs compared to other dopamine agonists. Compounds with 5,6 substitutions were found to be inactive in this model of food intake.

아네릭 에스. 피.(Arneric S. P.) 등의 문헌[Arch. Int. Pharmocodyn. Ther.,257, 263(1982)]은 2-아미노테트랄린 및 2-아미노인단 유사체를 개시하고, 여기에서 5,6 디메톡시 치환된 화합물은 맥관 평활근에서의 수축을 평가하는 분석에서 불활성제로서 개시된다.Aneric S. Arneric SP et al. Arch. Int. Pharmocodyn. Ther., 257 , 263 (1982) disclose 2-aminotetraline and 2-aminoindane analogues, wherein the 5,6 dimethoxy substituted compounds are inactive agents in assays to assess contraction in vascular smooth muscle. It is disclosed as.

바트나가 알. 케이.(Bhatnagar R. K.) 등의 문헌[Pharmacol., Biochem. Behav.,17(Suppl. 1),11(1982)]은 도파민 수용체와 상호작용하는 아미노인단을 포함하는 다양한 구조물의 SAR 연구를 개시한다. 5,6-디메톡시 인단이 불활성 화합물로서 개시되어 있다.Batnaga knows. Bhatnagar RK et al., Pharmacol., Biochem. Behav., 17 (Suppl. 1), 11 (1982) disclose SAR studies of various constructs, including aminoindans that interact with dopamine receptors. 5,6-dimethoxy indan is disclosed as an inert compound.

캐논 제이. 지.(Cannon J. G.) 등의 문헌[J. Med. Chem.,25, 858(1982)]은 4,7-디메톡시-2-아미노인단 및 이의 도파민성 및 심장혈관 작용을 개시한다.Canon Jay. Cannon JG et al., J. Med. Chem., 25 , 858 (1982) discloses 4,7-dimethoxy-2-aminoindane and its dopaminergic and cardiovascular action.

캐논 제이. 지.(Cannon J. G.) 등의 문헌[J. Med. Chem.,25, 1442(1982)]은 5,6 디메톡시 및 디하이드록시 인단의 합성 및 도파민 수용체 활성이 없음을 보여주는 생물학을 개시한다.Canon Jay. Cannon JG et al., J. Med. Chem., 25 , 1442 (1982) discloses the synthesis of 5,6 dimethoxy and dihydroxy indane and the biology showing no dopamine receptor activity.

캐논 제이. 지.(Cannon J. G.) 등의 문헌[J. Med. Chem.,27, 186(1984)]은 2-아미노-4,6-디하이드록시인단의 N-알킬화 유도체의 합성을 개시한다.Canon Jay. Cannon JG et al., J. Med. Chem., 27 , 186 (1984) discloses the synthesis of N-alkylated derivatives of 2-amino-4,6-dihydroxyindane.

캐논 제이. 지.(Cannon J. G.) 등의 문헌[J. Med. Chem.,28, 515(1985)]은 4-하이드록시 아미노인단의 용해를 개시한다.Canon Jay. Cannon JG et al., J. Med. Chem., 28 , 515 (1985), disclose the dissolution of 4-hydroxy aminoindane.

캐논 제이. 지.(Cannon J. G.) 등의 문헌[J. Med. Chem.,29, 2016(1986)]은 2-아미노인단(4,5 치환), 아미노테트랄린 및 벤즈[f]퀴놀린의 오르토(ortho) OH/메틸, 하이드록시메틸, 포르밀 또는 카복시 유도체를 개시한다.Canon Jay. Cannon JG et al., J. Med. Chem., 29 , 2016 (1986)] ortho OH / methyl, hydroxymethyl, formyl or carboxy derivatives of 2-aminoindane (4,5 substitution), aminotetraline and benz [f] quinoline To start.

핵셀 유.(Hacksell U.) 등의 문헌[J. Med. Chem.,24, 429(1981)]은 중심 도파민 수용체 자극제로서 일페놀성 2-아미노인단의 합성을 개시한다.Hacksell U. et al., J. Med. Chem., 24 , 429 (1981), disclose the synthesis of monophenolic 2-aminoindanes as central dopamine receptor stimulants.

마 스.(Ma S.) 등의 문헌[J. Pharmacol. Exp. Ther.,256, 751(1991)]은 4,5 위치에서 이치환을 주로 갖는 2-아미노인단의 도파민성 구조 활성 관계를 개시한다.Ma S. et al. J. Pharmacol. Exp. Ther., 256 , 751 (1991) discloses the dopaminergic structure activity relationship of 2-aminoindanes with predominantly disubstituted at 4,5 positions.

니콜 디. 이.(Nichole D. E.)의 문헌[J. Med. Chem.,33, 703(1990)]은 3,4 (메틸렌디옥시)암페타민의 비신경독성 테트랄린 및 인단 유사체를 개시한다.Nicole D. Nichole DE, J. Med. Chem., 33 , 703 (1990), discloses non-neurotoxic tetralin and indan analogs of 3,4 (methylenedioxy) amphetamine.

PCT 특허원 제 WO90/07490 호는 Br기와 함께 OCH3또는 OH를 갖는 방향족 치환을 갖는 2-아미노테트랄린 및 2-아미노인단을 개시한다.PCT patent application WO90 / 07490 discloses 2-aminotetralines and 2-aminoindanes having aromatic substitutions with OCH 3 or OH with Br groups.

1988년 3월 24일에 출원된 유럽 특허원 제 88302599.1 호는 본원에서 개시되지 않은 아민상에 이환 구조 및 메틸기를 갖는 항부정맥 아미노인단을 개시하고 있다.European Patent Application No. 88302599.1, filed March 24, 1988, discloses antiarrhythmic aminoindanes having bicyclic structures and methyl groups on amines not disclosed herein.

미국 특허 제 4,132,737 호는 트리플루오로메틸 치환된 1-아미노인단을 개시시하고(본 발명은 2-아미노인단임); 미국 특허 제 5,225,596 호는 치환된 테트랄린을 개시한다(본원에서는 치환되지 않고 사용됨).US Patent No. 4,132,737 discloses trifluoromethyl substituted 1-aminoindanes (the present invention is 2-aminoindanes); U.S. Patent 5,225,596 discloses substituted tetralin (used unsubstituted herein).

발명의 요약Summary of the Invention

한 측면에서, 본 발명은 하기 화학식 (I)의 화합물 및 약학적으로 허용가능한 염에 관한 것이다:In one aspect, the invention relates to a compound of formula (I) and a pharmaceutically acceptable salt:

상기 식에서,Where

R1및 R2는 독립적으로 H, C1-C8알킬 또는 C1-C8알킬아릴이고;R 1 and R 2 are independently H, C 1 -C 8 alkyl or C 1 -C 8 alkylaryl;

X는 CH2R3또는 NHSO2R4이고;X is CH 2 R 3 or NHSO 2 R 4 ;

Y는 수소, CH2R3, NHSO2R4, CONR1R2, SO2NR1R2, SO2CH3, 할로겐, OSO2CF3, SCH3또는 OCH3이고;Y is hydrogen, CH 2 R 3 , NHSO 2 R 4 , CONR 1 R 2 , SO 2 NR 1 R 2 , SO 2 CH 3 , halogen, OSO 2 CF 3 , SCH 3 or OCH 3 ;

R3는 NHSO2R4, SO2R4, CONR1R2또는 아릴이고; 및R 3 is NHSO 2 R 4 , SO 2 R 4 , CONR 1 R 2 or aryl; And

R4는 NR1R2, C1-C8알킬, 아릴 또는 C1-C8알킬아릴이다.R 4 is NR 1 R 2 , C 1 -C 8 alkyl, aryl or C 1 -C 8 alkylaryl.

또다른 측면에서, 본 발명은 라세미 혼합물을 포함하고 양 에난티오머로서 상기 화학식 (I)의 화합물 및 약학적으로 허용가능한 염에 관한 것이다. R1및 R2가 독립적으로 수소 및 저급 알킬(C1-C8알킬)이고; Y가 CONR1R2, SO2NR1R2및 SO2CH3(R1및 R2가 독립적으로 수소 및 저급 알킬이다)인 화학식 (I)의 구조물이 바람직하다.In another aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt comprising a racemic mixture and as positive enantiomers. R 1 and R 2 are independently hydrogen and lower alkyl (C 1 -C 8 alkyl); Preference is given to structures of the formula (I) in which Y is CONR 1 R 2 , SO 2 NR 1 R 2 and SO 2 CH 3 , wherein R 1 and R 2 are independently hydrogen and lower alkyl.

또다른 측면에서, 본 발명은 정신분열증으로 고통받고 있는 환자에게 치료학적으로 유효량의 화학식 (I)의 화합물을 투여함으로써 정신분열증을 치료하는 방법이다.In another aspect, the invention is a method of treating schizophrenia by administering to a patient suffering from schizophrenia a therapeutically effective amount of a compound of formula (I).

또다른 측면에서, 본 발명은 이러한 질환의 완화를 위해 치료학적으로 유효량의 화학식 (I)의 화합물을 대상에게 투여하는 것을 포함하는 치료가 필요한 환자에 있어서, 도파민 D3 수용체 활성과 관련된 중추 신경계 질환을 치료하는 방법에 관한 것이다. 전형적으로, 화학식 (I)의 화합물은 약학적으로 허용가능한 담체 또는 희석액을 포함하는 약학 조성물의 형태로 투여된다.In another aspect, the present invention provides a method for treating a central nervous system disorder associated with dopamine D3 receptor activity in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) to alleviate such a disease. To a method of treatment. Typically, the compound of formula (I) is administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.

또다른 측면에서, 본 발명은 약학적으로 허용가능한 담체 또는 희석액과 함께 유효량의 화학식 (I)의 화합물을 포함하는 도파민 D3 수용체 활성과 관련된 중추 신경계 질환을 치료하는 약학 조성물에 관한 것이다.In another aspect, the invention relates to a pharmaceutical composition for treating central nervous system diseases associated with dopamine D3 receptor activity comprising an effective amount of a compound of formula (I) together with a pharmaceutically acceptable carrier or diluent.

본 발명은 상기 서술된 바와 같이, 라세미 또는 순수한 에난티오머 형태로 화학식 (I)의 화합물 또는 약학적으로 허용가능한 염에 관한 것이다. X, Y, R1, R2, R3및 R4는 독립적으로 상기 언급된 바와 같이 선택된다.The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt in racemic or pure enantiomeric form, as described above. X, Y, R 1 , R 2 , R 3 and R 4 are independently selected as mentioned above.

알킬은 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 헵틸, 옥틸 및 이들의 이성질체 형태와 같은 1 내지 8개의 탄소 원자이다.Alkyl is 1 to 8 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomeric forms.

할로겐은 불소, 염소, 브롬 또는 요오드의 원자이다.Halogen is an atom of fluorine, chlorine, bromine or iodine.

아릴은 벤젠 및 하나 또는 두 개의 헤테로원자 N, O, S를 함유하는 5- 및 6-원환 방향족 헤테로환을 포함한다. 이들 아릴 그룹은 H, 하나 이상의 할로겐, CN, CF3, NO2, C(O)NR1R2, SO2NR1R2, NHC(O)-C1-3알킬 또는 SO2CH3와 같은 그룹으로 치환될 수 있다.Aryl includes 5- and 6-membered ring aromatic heterocycles containing benzene and one or two heteroatoms N, O, S. These aryl groups include H, at least one halogen, CN, CF 3 , NO 2 , C (O) NR 1 R 2 , SO 2 NR 1 R 2 , NHC (O) -C 1-3 alkyl or SO 2 CH 3 They may be substituted by the same group.

약학적으로 허용가능한 염은 무기 및 유기 산의 염을 포함한다. 바람직한 약학적으로 허용가능한 염은 하기의 산의 염을 포함한다; 메탄설폰산, 염산, 브롬산, 황산, 인산, 질산, 벤조산, 시트르산, 타르타르산, 푸말산 또는 말레산.Pharmaceutically acceptable salts include salts of inorganic and organic acids. Preferred pharmaceutically acceptable salts include salts of the following acids; Methanesulfonic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, citric acid, tartaric acid, fumaric acid or maleic acid.

화학식 (I)의 화합물은 경구적으로 또는 비경구적으로 활성이다. 당해 기술분야의 숙련자에게 공지되어 있듯이, 경구적으로 화학식 (I)의 화합물은 정제 또는 캡슐과 같은 고형물로 투여될 수 있거나 엘릭시르(elixir), 시럽 또는 현탁액과 같은 액체로 투여될 수 있다. 화학식 (I)의 화합물은 고형물로 투여되는 것이 바람직하고, 정제가 바람직하다.Compounds of formula (I) are active orally or parenterally. As is known to those skilled in the art, the compounds of formula (I) can be administered orally in solids such as tablets or capsules or in liquids such as elixir, syrups or suspensions. The compound of formula (I) is preferably administered as a solid, with tablets being preferred.

전형적으로, 화학식 (I)의 화합물은 하루에 1 내지 3회, 한 사람당 약 0.25 내지 약 100mg의 양으로 투여할 수 있다. 분할 투여형태로, 약 10 내지 약 50mg/일이 바람직하다.Typically, the compound of formula (I) may be administered in an amount of about 0.25 to about 100 mg per person, one to three times a day. In divided dosage forms, from about 10 to about 50 mg / day is preferred.

정확한 투여량 및 투여횟수는 당해 기술분야의 숙련자에게 잘 공지된 바와 같이, 사용되는 화학식 (I)의 특정 화합물, 치료되는 특정 조건, 치료되는 조건의 심각도, 특정 환자의 나이, 체중, 일반적인 물리적 상태, 개인이 취할 수 있는 다른 약물에 따라 다르고, 환자의 혈중의 활성 화합물의 혈량 또는 혈농도 및/또는 치료되는 특정 조건에 대한 환자의 반응을 측정함으로써 더 정확히 결정될 수 있다.The exact dosage and frequency of administration are well known to those skilled in the art, including the specific compound of formula (I) used, the specific condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient. Depending on the other drugs an individual can take, it can be more accurately determined by measuring the blood volume or blood concentration of the active compound in the patient's blood and / or the patient's response to the particular condition being treated.

따라서, 약학적으로 허용가능한 담체, 희석액 또는 완충액과 함께 본 발명의 화합물은 진단된 생리학적 조건과 관련된 중추 신경계 질환을 완화시키는데 효과적인 치료학적 또는 약리학적 유효량으로 투여된다. 이 화합물은 정맥내, 근육내, 국소적으로, 피부 패치(patch)와 같이 피부를 통해, 협측으로 또는 경구적으로 인간 또는 다른 척추동물에게 투여될 수 있다.Thus, the compounds of the present invention, together with pharmaceutically acceptable carriers, diluents or buffers, are administered in a therapeutically or pharmacologically effective amount effective to alleviate central nervous system diseases associated with diagnosed physiological conditions. The compound may be administered to humans or other vertebrates intravenously, intramuscularly, topically, through the skin such as skin patches, buccally or orally.

본 발명의 조성물은 인간 및 다른 척추동물에게 정제, 캡슐, 알약, 분말, 과립제, 살균된 비경구용액 또는 현탁액, 경구액 또는 현탁액, 화합물의 적합한 양을 함유하는 수중유적형 유화액 및 유중수적형 유화액, 및 유체 현탁액 또는 용액의 좌약과 같은 단위 투여 형태로 제조될 수 있다.The compositions of the present invention are tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral or suspensions, oil-in-water emulsions and water-in-oil emulsions containing suitable amounts of the compound for humans and other vertebrates. , And in unit dosage forms such as suppositories of fluid suspensions or solutions.

경구 투여의 경우, 고형물 또는 유체 단위 투여 형태가 제조될 수 있다. 정제와 같은 고형 조성물의 제조시, 화합물은 활석, 스테아르산 마그네슘, 인산 이칼슘, 알루미늄 규산 마그네슘, 황산 칼슘, 전분, 락토즈, 아카시아, 메틸셀룰로즈, 및 기능적으로 유사한 약학 희석액 또는 담체 물질과 같은 통상적인 성분들과 혼합될 수 있다. 화합물을 불활성 약학 희석액과 혼합하고 이 혼합물을 적합한 크기의 경질 젤라틴 캡슐안에 충진시킴으로써 캡슐을 제조한다. 허용가능한 채소유, 경급 액체 바셀린 또는 다른 불활성유와 함께 화합물의 슬러리를 기계적으로 캡슐화함으로써 연질 젤라틴 캡슐을 제조한다.For oral administration, solid or fluid unit dosage forms can be prepared. In the preparation of solid compositions such as tablets, the compounds may be prepared by conventional methods such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar pharmaceutical diluents or carrier materials. It can be mixed with the phosphorus components. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into hard gelatine capsules of suitable size. Soft gelatin capsules are prepared by mechanically encapsulating a slurry of the compound with an acceptable vegetable oil, a light liquid petrolatum or other inert oil.

시럽, 엘릭시르 및 현탁액과 같은 경구 투여용 액체 단위 투여 형태가 제조될 수 있다. 이 형태를 설탕, 방향족 방향제 및 보존제와 함께 수성 부형제(vehicle)에 용해시켜 시럽을 형성할 수 있다. 현탁액은 아카시아, 트라가칸트(tragacanth), 메틸셀룰로즈 등과 같은 현탁 제제에 의해 수성 부형제와 함께 제조될 수 있다.Liquid unit dosage forms for oral administration such as syrups, elixirs and suspensions can be prepared. This form can be dissolved in an aqueous vehicle with sugars, aromatic fragrances and preservatives to form syrups. Suspensions can be prepared with aqueous excipients by suspending agents such as acacia, tragacanth, methylcellulose and the like.

비경구적 투여의 경우, 유체 단위 투여 형태가 화합물 및 살균된 부형제를 사용하여 제조될 수 있다. 용액을 제조하는 경우, 주사를 위해 화합물을 물에 용해시키고, 적합한 바이알 또는 암풀(ampoule)에 충진시키고 밀봉하기 전에 필터 살균할 수 있다. 국부 마취제, 보존제 및 완충제와 같은 보조제를 부형제에 용해할 수 있다. 조성물을 바이알에 충진시킨후 냉동시키고, 진공하에서 물을 제거할 수 있다. 이어, 동결 건조된 분말을 사용하기 전에 바이알에 밀봉하고 재구성할 수 있다.For parenteral administration, fluid unit dosage forms can be prepared using the compound and sterile excipients. When preparing the solution, the compound can be dissolved in water for injection, filter sterilized before filling and sealing in a suitable vial or ampoule. Adjuvants such as local anesthetics, preservatives and buffers may be dissolved in the excipient. The composition can be frozen after filling into a vial and the water removed under vacuum. The lyophilized powder can then be sealed in a vial and reconstituted prior to use.

화학적 합성: Chemical synthesis :

시판되는 4-브로모벤질브롬화물(1)을 t-부틸 아세테이트의 리튬 에놀레이트에 의해 알킬화하고(반응식 1), 후속적으로 트리플루오로아세트산에 의해 탈에스테르화하여 카복실산(2)을 수득하였다. 티오닐 클로라이드를 사용하는 아실 클로라이드로의 전환 및 염화 알루미늄에 의한 후속적인 프리델-크레프트(Friedel-Craft) 환화반응에 의해 인다논(3)이 수득된다. 6-브로모-1-인단(3)을 4단계에서 89% 총 수율로 수득하였다. 6-브로모-1-인다논(3)을 수소화나트륨 및 디메틸 카보네이트를 사용하여 카복실화하여 β-케토-메틸에스테르(4)를 수득하였다. 이 방법을 사용하여 대규모(0.67몰)로 고수율(97%)을 수득하였다. β-케토-에스테르를 소디움 보로하이드리드 및 메탄올로 환원하여 히드록시-에스테르(5)를 수득하였다.Commercially available 4-bromobenzylbromide (1) was alkylated with lithium enolate of t-butyl acetate (Scheme 1) and subsequently deesterified with trifluoroacetic acid to give carboxylic acid (2). . Indanone (3) is obtained by conversion to acyl chloride using thionyl chloride and subsequent Friedel-Craft cyclization with aluminum chloride. 6-Bromo-1-indane (3) was obtained in 4 steps with 89% total yield. 6-Bromo-1-indanonone (3) was carboxylated using sodium hydride and dimethyl carbonate to give β-keto-methylester (4). This method was used to obtain high yield (97%) on a large scale (0.67 moles). β-keto-ester was reduced with sodium borohydride and methanol to give hydroxy-ester (5).

폴리인산에 의한 β-히드록시-에스테르의 탈수는 60분이내에 고수율로 불포화 에스테르(6)를 제공한다(문헌[Vebrel, J., Carrie, R. Synthese de methoxycarbonylindenes, dihydro-1,2 naphthalenes et benzocycloheptene, Bull. Soc. Chim. Fr., 1982, ptII, 116-24] 참조). 이 에스테르의 탈메틸화는 수성 메탄설폰산 및 포름산에 의해 수행되어(문헌[Loev, B., Acid Catalysed Hydrolysis of Esters, Chem. and Ind. 1964, 193-94] 참조) 고수율로 (7)을 제조시킨다. 유사한 결과가 삼브롬화붕소를 사용하여 수득되었다.Dehydration of β-hydroxy-esters by polyphosphoric acid provides unsaturated esters (6) in high yield within 60 minutes (Vebrel, J., Carrie, R. Synthese de methoxycarbonylindenes, dihydro-1,2 naphthalenes et benzocycloheptene, Bull. Soc. Chim. Fr., 1982, ptII, 116-24). Demethylation of this ester is carried out with aqueous methanesulfonic acid and formic acid (see Loev, B., Acid Catalysed Hydrolysis of Esters, Chem. And Ind. 1964, 193-94) to obtain (7) in high yield. To manufacture. Similar results were obtained using boron tribromide.

(S)-BINAP-루테늄(II) 디아세테이트의 비대칭적 수소화(오타 티(Ohta T) 등의 문헌[Asymmetric hydrogentation of unsaturated carboxylic acids..., J. Org. Chem., 1987, 52, 3174-76] 및 기타무라 엠.(Kitamura M.) 등의 문헌[Practical synthesis of BINAP-ruthenium dicarboxylate complexes, J. Org. Chem. 1992, 57, 4053-54] 참조)는 고순도의 에난티오머(95:5의 비)로 (8)을 제공하였다. 디에틸 에테르/메탄올로부터 (R)-(+)-α-메틸벤질아민/인다노산 염의 재결정화는 광학적으로 순수한 산을 제공하였다. 에난티오머 비를 환원된 산(알콜)의 키랄 HPLC 분리에 의해 평가하였다.Asymmetric hydrogenation of unsaturated carboxylic acids, et al., J. Org. Chem., 1987, 52, 3174- (S) -BINAP-ruthenium (II) diacetate. 76 and Kitamura M. et al. (See Practical synthesis of BINAP-ruthenium dicarboxylate complexes, J. Org. Chem. 1992, 57, 4053-54) for high purity enantiomers (95: 5 (8) is provided. Recrystallization of the (R)-(+)-α-methylbenzylamine / indanoic acid salt from diethyl ether / methanol gave an optically pure acid. Enantiomer ratios were evaluated by chiral HPLC separation of the reduced acid (alcohol).

이 시점에서, 카복실산(8)은 디페닐포스포릴 아지드(니노미야등의 문헌[A new convenient reagent for a modified Curtius reaction, Tetrahed, 1974, 30, 2154-57]참조)에 의해 커티우스(Curtius) 재배열되어, t-부틸 카바메이트(9)를 수득하고 트리플루오로아세트산과 함께 환류되어 1급 아민(10)으로 전환되었다. 브로모프로판으로 디알킬화하여 3급 아민(11)을 수득하였다. (S)-(+)-5-브로모-2-N,N-디프로필아미노인단의 전체 합성은 9%의 전체 수율로 10단계를 포함한다.At this point, the carboxylic acid (8) is curtius by diphenylphosphoryl azide (see A new convenient reagent for a modified Curtius reaction, Tetrahed, 1974, 30, 2154-57). Rearrangement afforded t-butyl carbamate 9 and refluxed with trifluoroacetic acid to convert to primary amine 10. Dialkylation with bromopropane gave tertiary amine (11). The overall synthesis of (S)-(+)-5-bromo-2-N, N-dipropylaminoindan comprises 10 steps in 9% overall yield.

(S)-(+)-5-브로모-2-N,N-디프로필아미노인단(11)은 몇가지 에난티오머적으로 순수한 유사체를 제조하기 위한 중간체로서 사용되었다. 3급 부틸리튬에 의한 금속 할로겐 교환은 리튬 음이온을 형성하고, 이것은 트리메틸실일이소시아네이트로 처리되어 5-카복스아미드 유사체(12)를 형성하였다. 이것은 보란-메틸설파이드에 의해 1급 아민(14)으로 환원되었다. 별도의 일련의 반응에서 리튬 음이온(11)은 파라포름알데히드로 처리되어(문헌[Rec. Trav. Pays-Bays, 1965, 1200]) 5-하이드록시메틸 유사체(13)를 수득한후 메탄설포닐 클로라이드를 사용하여 메실레이트(15)로 전환되었다. 이 메실레이트는 다음으로 벤젠설핀산, 나트륨염을 사용하여 페닐 설폰(16)으로 전환되었다. 이것은 또한 시안화나트륨으로 메실레이트(15)를 처리함으로써 얻어진 아세토니트릴을 통하여 아세트아미드(17)로 전환되었다. 아세토니트릴 중간체를 수산화나트륨 및 과산화수소에 의해 수화시켜 화합물(17)을 산출시켰다(카치(Cacchi, S.)등의 문헌[Amides from nitriles using basic hydrogen peroxide under phase-transfer catalyzed conditions, Synthesis 1980, 243-44]).(S)-(+)-5-bromo-2-N, N-dipropylaminoindane (11) was used as an intermediate to prepare some enantiomerically pure analogs. Metal halide exchange with tertiary butyllithium formed a lithium anion, which was treated with trimethylsilyl isocyanate to form the 5-carboxamide analog (12). This was reduced to the primary amine 14 by borane-methylsulfide. In a separate series of reactions, the lithium anion (11) was treated with paraformaldehyde (Rec. Trav. Pays-Bays, 1965, 1200) to yield 5-hydroxymethyl analog (13), followed by methanesulfonyl The chloride was used to convert to mesylate (15). This mesylate was then converted to phenyl sulfone (16) using benzenesulfinic acid, sodium salt. It was also converted to acetamide (17) through acetonitrile obtained by treating mesylate (15) with sodium cyanide. The acetonitrile intermediate was hydrated with sodium hydroxide and hydrogen peroxide to yield compound 17 (Cacchi, S. et al., Amines from nitriles using basic hydrogen peroxide under phase-transfer catalyzed conditions, Synthesis 1980, 243-). 44]).

반응식 3은 5-하이드록시메틸 유사체(13)으로부터 출발하는 화합물(18-22)의 제법을 도시한다. 6-브로모-2-인드-(1-엔)오산(7)으로부터 제조된 이 유사체는 (R)-BINAP-루테늄(II) 디아세테이트를 사용하여 비대칭적으로 수소화되어 (R)-(-)-5-브로모인다노산(8)을 산출하였다. 카복실산(8)은 디페닐포스포릴 아지드의 도움으로 커티우스(Curtius) 재배열을 수행하여 t-부틸 카바메이트(9)를 산출한후 트리플루오로아세트산으로의 환류에 의해 1급 아민(10)으로 전환되었다. 브로모프로판으로 디알킬화하여 3급 아민(11)을 수득하였다. 3급 부틸리튬에 의한 금속 할로겐 교환은 리튬 음이온을 산출하고, 이것은 파라포름알데히드로의 처리에 의해 5-하이드록시메틸 유사체(13)가 수득되었다.Scheme 3 shows the preparation of compounds (18-22) starting from 5-hydroxymethyl analog (13). This analog, prepared from 6-bromo-2-ind- (1-en) oxane (7), was asymmetrically hydrogenated using (R) -BINAP-ruthenium (II) diacetate to give (R)-(- ) -5-bromoindanoic acid (8) was calculated. The carboxylic acid (8) was subjected to Curtius rearrangement with the help of diphenylphosphoryl azide to yield t-butyl carbamate (9), followed by reflux to trifluoroacetic acid (10). ) Dialkylation with bromopropane gave tertiary amine (11). Metal halide exchange with tertiary butyllithium yielded a lithium anion, which gave 5-hydroxymethyl analogue 13 by treatment with paraformaldehyde.

(R)-(-)-5-하이드록시메틸-2-N,N-디프로필아미노인단(13)은 테트라하이드로푸란중의 티오닐 클로라이드를 사용하여 클로로메틸 유사체(18)(96% 수율)로 전환되었다(문헌[Chem. Rev. 1963, 63, 557]). 염기성 용액중에서 염화물의 4-브로모티오페놀로의 치환에 의해 (R)-(-)-5-(4-브로모벤젠)티오메틸-2-N,N-디프로필아미노인단(19)가 93%의 수율로 수득되었다. 파라세트산을 사용하여 설파이드를 79%의 수율로 산화시켜 설폰(20)을 수득하였다. 아릴 브로마이드와 포름아미드의 팔라듐 커플링은 (R)-(-)-5-(4-카복시미도벤젠)설포닐메틸-2-N,N-디프로필아미노인단(21)을 수득하였다. 티타늄 테트라클로라이드 및 트리에틸아민을 사용하여 카복시미드의 탈수(문헌[Tetrahed. Lett. 1971, 1501])는 시아노 유사체(22)를 78%의 수율로 제공하였다.(R)-(-)-5-hydroxymethyl-2-N, N-dipropylaminoindane (13) is a chloromethyl analog (18) (96% yield) using thionyl chloride in tetrahydrofuran. (Chem. Rev. 1963, 63, 557). Substitution of (R)-(-)-5- (4-bromobenzene) thiomethyl-2-N, N-dipropylaminoindan (19) by substitution of chloride with 4-bromothiophenol in the basic solution Obtained in 93% yield. The sulfide 20 was oxidized using paraacetic acid to yield a yield of 79%. Palladium coupling of aryl bromide with formamide yielded (R)-(-)-5- (4-carboxymididobenzene) sulfonylmethyl-2-N, N-dipropylaminoindane (21). Dehydration of carboxymides using titanium tetrachloride and triethylamine (Tetrahed. Lett. 1971, 1501) provided cyano analog 22 in 78% yield.

반응식 4는 (R)-(-)-5-브로모-2-N,N-디프로필아미노인단(11)으로 출발하여 5-위치에서 금속/할로겐 교환을 통하여 리시에이트되고, 디페닐포스포릴아지드로 처리되는, 화합물(24-39)의 제법을 도시한다. 생성된 아지드는 리튬 알루미늄 하이드라이드와 동일한 포트중에서 환원시켜(문헌[Chem. Pharm. Bull. 1986, 1524])(R)-(-)-5-아미노-2-N,N-디프로필아미노인단(23)(41%)을 수득하였다. 일급 아민을 벤젠설포닐 클로라이드 또는 4-클로로벤젠설포닐 클로라이드로 설포닐화시켜 각각 24 및 25를 수득하였다.Scheme 4 begins with (R)-(-)-5-bromo-2-N, N-dipropylaminoindan (11) and is lysed via metal / halogen exchange at the 5-position and diphenylphosphoryl The preparation method for compound (24-39), which is treated with azide, is shown. The resulting azide was reduced in the same pot as lithium aluminum hydride (Chem. Pharm. Bull. 1986, 1524) (R)-(-)-5-amino-2-N, N-dipropylaminoindane (23) (41%) was obtained. The primary amine was sulfonylated with benzenesulfonyl chloride or 4-chlorobenzenesulfonyl chloride to give 24 and 25, respectively.

(R)-(-)-5-브로모-2-N,N-디프로필아미노인단(11)은 3급 부틸리튬으로 금속/할로겐 교환을 통해 리시에이트된다음 트리메틸실일이소시아네이트로 처리되어 5-카복스아미드 유사체(12)를 수득하였다. 이것은 보란-메틸설파이드로 1급 아민(14)으로 환원되었다. 유사체(26) 내지 (39)를 수득하기 위해 1급 아민(14)는 다양한 설포닐 클로라이드로 설포닐화되었다.(R)-(-)-5-bromo-2-N, N-dipropylaminoindane (11) is lysed through metal / halogen exchange with tertiary butyllithium and then treated with trimethylsilyl isocyanate to give 5- Carboxamide analogue 12 was obtained. This was reduced to primary amine 14 with borane-methylsulfide. Primary amines 14 were sulfonylated with various sulfonyl chlorides to yield analogs 26-39.

반응식 5는 디메틸 말로네이트로 출발하여 상 전이 조건하에서 프로파길 브로마이드로 디알킬화되어 디에스테르(40)를 수득하고, 탈카복실레이트화되어(문헌[A.P. Krapcho and A.J. Lovey, Tetrahed. Lett. 1973, 957; A.P. Krapcho, J.F. Weimaster, J.M. Eldridge, E.G.E. Jahngen, Jr., A.J. Lovey, and W.P. Stephens, J. Org. Chem. 1978, 43, 138]) 모노에스테르(41)를 수득하는 화합물(53-56)의 제법을 도시한다. 수성 수산화나트륨에 의해 에스테르를 가수분해하여 산(42)을 수득하였고, 디페닐 포스포릴 아지드로의 개질된 커티우스 재배열을 통하여 t-부틸카바메이트(43)로 전환시켰다(문헌[K. Ninomiya, T. Shioiri, and S. Yamada, Tetrahed. 1974, 30, 2151]). t-부틸카바메이트는 트리플루오로에스트산으로 4-아미노-1,6-헵타디인(44)으로 가수분해되었고, 테트라하이드로푸란중의 트리플루오로아세트산 무수물 및 트리에틸아민을 사용하여 상기 아민은 트리플루오로아세트아미드(45)로서 보호되었다.Scheme 5 starts with dimethyl malonate and dialkylates with propargyl bromide under phase transition conditions to yield diesters 40 and decarboxylates (AP Krapcho and AJ Lovey, Tetrahed. Lett. 1973, 957). AP Krapcho, JF Weimaster, JM Eldridge, EGE Jahngen, Jr., AJ Lovey, and WP Stephens, J. Org. Chem. 1978, 43, 138)) Compounds to Obtain Monoester (41) (53-56) It shows the manufacturing method of. Hydrolysis of the ester with aqueous sodium hydroxide yielded the acid (42), which was converted to t-butylcarbamate (43) via a modified Curtis rearrangement to diphenyl phosphoryl azide (K. Ninomiya). , T. Shioiri, and S. Yamada, Tetrahed. 1974, 30, 2151]. t-Butyl carbamate was hydrolyzed to 4-amino-1,6-heptadyin (44) with trifluoroestic acid and the amine using trifluoroacetic anhydride and triethylamine in tetrahydrofuran Was protected as trifluoroacetamide (45).

에탄올중의 윌킨슨 촉매(Wilkinson's catalyst)를 사용하여 디인(45)은 2-부틴-1,4-디아세테이트(46)으로 환화되어(문헌[P. Magnus and D. Witty, Tetrahed. Lett. 1993, 34, 23]) 인단(47)을 수득하였다. 트리플루오로아세트아미드 및 아세테이트 잔기는 수성 메탄올중에서 수산화칼륨으로 가수분해되어 조 아민(48)을 수득하였고, 아세토니트릴중에 1-브로모프로판으로 디알킬화되어 화합물(46)으로부터 디프로필아민(49)을 81%의 전체 수율로 수득하였다. 디올(49)은 티오닐 클로라이드에 의해 5,6-비스(클로로메틸)인단(50)으로 전환되었다.Using Wilkinson's catalyst in ethanol, the diyne 45 was cyclized to 2-butyne-1,4-diacetate 46 (P. Magnus and D. Witty, Tetrahed. Lett. 1993, 34, 23]) indan 47 was obtained. Trifluoroacetamide and acetate residues were hydrolyzed with potassium hydroxide in aqueous methanol to give crude amine 48 and dialkylated with 1-bromopropane in acetonitrile to dipropylamine (49) from compound (46). Was obtained in 81% overall yield. Diol 49 was converted to 5,6-bis (chloromethyl) indane 50 by thionyl chloride.

5,6-비스(클로로메틸)인단(50)은 디메틸포름아미드중에서 소디움 아지드에 의해 디아지드(51)로 전환되었다. 디아지드는 유리되지 않았지만, 메틸-t-부틸에테르로 추출되었고, 리튬 알루미늄 하이드라이드로 환원되었다. 상기 반응은 불완전한 환원을 나타내었고, 따라서 메탄올 환원중에서 마그네슘으로 처리되어(문헌[S.N. Maiti, P. Spevak, and A.V. Narender Reddy, Syn. Comm. 1988, 18, 1201]), 조 디아민(52)을 수득하였다. 상기 디아민은 피리딘중의 다양한 설포닐 클로라이드와 반응되어 비스(설폰아미드)(53, 54 및 55)를 수득하였다.5,6-bis (chloromethyl) indane 50 was converted to diazide 51 by sodium azide in dimethylformamide. Diazide was not free, but was extracted with methyl-t-butylether and reduced with lithium aluminum hydride. The reaction showed incomplete reduction and thus treated with magnesium in methanol reduction (SN Maiti, P. Spevak, and AV Narender Reddy, Syn. Comm. 1988, 18, 1201) to give crude diamine (52). Obtained. The diamine was reacted with various sulfonyl chlorides in pyridine to give bis (sulfonamide) 53, 54 and 55.

5,6-비스(클로로메틸)인단(56)은 디메틸포름아미드중에서 소디움 벤젠설피네이트로 비스(메틸페닐설폰)으로 전환되었다.5,6-bis (chloromethyl) indane 56 was converted to bis (methylphenylsulfone) with sodium benzenesulfinate in dimethylformamide.

절차는 하기의 실시예에서 반응식 1 내지 5의 화학식으로 도시된다. 화합물은 반응식중에서 번호로 되어 나타내어진다.The procedure is shown in the formulas of Schemes 1-5 in the Examples below. Compounds are represented by numbers in the scheme.

절차 1Procedure 1

3-(4-브로모페닐)프로피온산(2)3- (4-Bromophenyl) propionic acid (2)

t-부틸 아세테이트(159ml, 1180mmol)을 -78℃에서 테트라하이드로푸란중의 리튬 디이소프로필아미드(941mmol)에 가한후 다시 4-브로모벤질브로마이드(200g, 784mmol)에 가한다. 욕조온도를 4시간동안 -15℃로 유지하고, 반응을 염화암모늄으로 급냉시켰다. 상기 혼합물을 디에틸 에테르로 추출하였고, 유기층을 희석 염산, 물 및 염수로 세척하였고, 황산나트륨으로 건조시켜 엷은 기름을 수득하였다. 이것을 트리플루오로아세트산(150ml, 1960mmol)으로 1시간동안 환류시켰다. 트리플루오로아세트산을 진공하에서 제거하였고, 잔사를 디에틸 에테르와 수성 수산화나트륨사이로 분배시켰다. 수성층을 농축 염산으로 0℃에서 산성화하였고, 디에틸 에테르로 추출하였다. 유기층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하여 진공하에서 용매를 제거한 후에 백색 고형물을 얻었다(167g, 93%), 융점 132 내지 134℃.t-Butyl acetate (159 ml, 1180 mmol) was added to lithium diisopropylamide (941 mmol) in tetrahydrofuran at −78 ° C. and again to 4-bromobenzylbromide (200 g, 784 mmol). The bath temperature was kept at -15 [deg.] C. for 4 hours and the reaction was quenched with ammonium chloride. The mixture was extracted with diethyl ether and the organic layer was washed with dilute hydrochloric acid, water and brine and dried over sodium sulfate to give a pale oil. This was refluxed with trifluoroacetic acid (150 ml, 1960 mmol) for 1 hour. Trifluoroacetic acid was removed under vacuum and the residue partitioned between diethyl ether and aqueous sodium hydroxide. The aqueous layer was acidified at 0 ° C. with concentrated hydrochloric acid and extracted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate to remove the solvent under vacuum to give a white solid (167 g, 93%), melting point 132-134 ° C.

절차 2Procedure 2

6-브로모-1-인다논(3)6-bromo-1-indanon (3)

3-(4-브로모페닐)프로피온산(162g, 706mmol) 및 티오닐 클로라이드(155ml, 2120mmol)을 90분동안 환류시켰다. 티오닐 클로라이드를 다음으로 진공하에서 제거하여 호박색 기름을 수득하였다. 이 기름, 염화알루미늄(109g, 816mmol) 및 디클로로메탄(1000ml)을 90분동안 환류한다음 얼음상에 부었다. 희석 염산을 가했고, 상기 혼합물을 디에틸 에테르로 추출하였다. 유기층을 2N 염산, 물, 수성 중탄산나트륨, 물 및 염수로 세척하였다. 생성물을 25 x 7cm 실리카겔 칼럼상에서 플래쉬 크로마토그래피하였고, 에틸 아세테이트/디클로로메탄(5:95)으로 용출하여 진공하에서 용매를 제거한 후에 엷은 갈색 고형물을 얻었다(142g, 95%), 융점 107 내지 109℃.3- (4-bromophenyl) propionic acid (162 g, 706 mmol) and thionyl chloride (155 ml, 2120 mmol) were refluxed for 90 minutes. Thionyl chloride was then removed under vacuum to give amber oil. This oil, aluminum chloride (109 g, 816 mmol) and dichloromethane (1000 ml) were refluxed for 90 minutes and then poured on ice. Dilute hydrochloric acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate, water and brine. The product was flash chromatographed on a 25 x 7 cm silica gel column and eluted with ethyl acetate / dichloromethane (5:95) to remove the solvent under vacuum to give a pale brown solid (142 g, 95%), melting point 107-109 ° C.

절차 3Procedure 3

6-브로모-2-카복시메틸-1-인다논(4)6-bromo-2-carboxymethyl-1-indanon (4)

테트라하이드로푸란(1200ml)중의 6-브로모-1-인다논(142g, 672mmol)을 디메틸 카보네이트(143ml, 1680mmol), 수소화나트륨(80.6g, 2020mmol, 60% 기름, 무게를 단후에 펜탄으로 세척됨) 및 테트라하이드로푸란(1200ml)를 환류시키면서 천천히 가했다. 혼합물을 2.5시간동안 환류한 후에, 아세트산(240ml)을 0℃에서 적가한다음 실온으로 승온하였다. 상기 혼합물을 디에틸 에테르/디클로로메탄과 희석 수성 염산사이에서 분배하였다. 유기층을 2N 염산, 물, 수성 중탄산나트륨 및 염수로 세척한다음 황산나트륨상에서 건조하여 진공하에서 용매를 제거한 후에 갈색 고형물을 얻었다(176g, 97%, 조생성물), 융점 124.5 내지 127.5℃.1H-NMR(300MHz, CDCl3) (약 3:1의 에놀 대 케톤 호 변이체의 비) 7.91(d, 0.27H), 7.77(d, 0.73H, J=1.8), 7.73(dd, 0.27H), 7.54(dd, 0.73H, J=8.1, 1.8), 7.39(d, 0.27H), 7.34(d, 0.73H, J=7.9), 3.86(s, 2.19H), 3.83(m,0.27H), 3.80(s,0.81H), 3.50(m,0.27H), 3.47(s,1.46H), 3.32(m,0.27H).6-bromo-1-indanonone (142g, 672mmol) in tetrahydrofuran (1200ml) was washed with dimethyl carbonate (143ml, 1680mmol), sodium hydride (80.6g, 2020mmol, 60% oil, weighed and then pentane ) And tetrahydrofuran (1200 ml) were added slowly while refluxing. After refluxing the mixture for 2.5 hours, acetic acid (240 ml) was added dropwise at 0 ° C. and then warmed to room temperature. The mixture was partitioned between diethyl ether / dichloromethane and dilute aqueous hydrochloric acid. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate and brine and then dried over sodium sulfate to remove the solvent under vacuum to give a brown solid (176 g, 97%, crude product), melting point 124.5-127.5 ° C. 1 H-NMR (300 MHz, CDCl 3 ) (ratio of enol to ketone mutants of about 3: 1) 7.91 (d, 0.27H), 7.77 (d, 0.73H, J = 1.8), 7.73 (dd, 0.27H ), 7.54 (dd, 0.73H, J = 8.1, 1.8), 7.39 (d, 0.27H), 7.34 (d, 0.73H, J = 7.9), 3.86 (s, 2.19H), 3.83 (m, 0.27H ), 3.80 (s, 0.81 H), 3.50 (m, 0.27 H), 3.47 (s, 1.46 H), 3.32 (m, 0.27 H).

절차 4Procedure 4

6-브로모-2-카복시메틸-1-하이독시인단(5)6-Bromo-2-carboxymethyl-1-hydoxyindane (5)

6-브로모-2-카복시메틸-1-인다논(139g, 650mmol), 메탄올(1100ml) 및 테트라하이드로푸란(200ml)을 0℃에서 교반하였다. 소디움 보로하이드라이드(9.30g, 245mmol)를 45분동안 부분적으로 가했고, 추가의 45분동안 교반하였다. 소디움 보로하이드라이드(12.4g, 326mmol)을 45분동안 부분적으로 가했고, 추가의 60분동안 교반하였다. 물을 가했고, 용매를 진공하에서 35℃에서 제거하였다. 잔사를 디에틸 에테르와 물로 분배하였다. 유기층을 물 및 염수로 세척한다음 황산나트륨상에서 건조시켰다. 조생성물을 30 x 7cm 실리카겔 칼럼상에서 플래쉬 크로마토그래피하였고, 디클로로메탄/에틸 아세테이트/헥산(1:2:5)으로 용출하여 오랜지색 왁스를 수득하였다(99.6g, 57%).1H-NMR(300MHz, CDCl3) (약 1:1 시스 내지 트랜스 부분질체의 비) 7.55(s, 0.43H), 7.51(s, 0.57H), 7.39(t, 0.57H, J=8.1), 7.39(t, 0.43H, J=8.1), 7.13(d, 0.43H, J=8.1), 7.08(d, 0.57H, J=8.1), 5.44(d, 0.57H, J=6.9), 5.30(d, 0.43H, J=6.0), 3.79(s, 1.71H), 3.77(s, 1.29H), 3.45-2.95(m.3H), 2.87(s, 1H).6-Bromo-2-carboxymethyl-1-indanon (139 g, 650 mmol), methanol (1100 ml) and tetrahydrofuran (200 ml) were stirred at 0 ° C. Sodium borohydride (9.30 g, 245 mmol) was added in part for 45 minutes and stirred for an additional 45 minutes. Sodium borohydride (12.4 g, 326 mmol) was added in part for 45 minutes and stirred for an additional 60 minutes. Water was added and the solvent was removed at 35 ° C. under vacuum. The residue was partitioned between diethyl ether and water. The organic layer was washed with water and brine and then dried over sodium sulfate. The crude product was flash chromatographed on a 30 × 7 cm silica gel column and eluted with dichloromethane / ethyl acetate / hexanes (1: 2: 5) to give an orange wax (99.6 g, 57%). 1 H-NMR (300 MHz, CDCl 3 ) (ratio of about 1: 1 cis to trans subpolymer) 7.55 (s, 0.43 H), 7.51 (s, 0.57 H), 7.39 (t, 0.57 H, J = 8.1) , 7.39 (t, 0.43H, J = 8.1), 7.13 (d, 0.43H, J = 8.1), 7.08 (d, 0.57H, J = 8.1), 5.44 (d, 0.57H, J = 6.9), 5.30 (d, 0.43H, J = 6.0), 3.79 (s, 1.71 H), 3.77 (s, 1.29 H), 3.45-2.95 (m. 3 H), 2.87 (s, 1H).

절차 5Procedure 5

6-브로모-2-카복시메틸-1-인덴(6)6-bromo-2-carboxymethyl-1-indene (6)

6-브로모-2-카복시메틸-1-하이독시인단(99.4g, 367mmol)을 60분동안 폴리포스포르산(475g)으로 가열하였다(기름 욕조 70℃, 반응온도를 80℃로 상승하는 발열). 반응물을 다음으로 물에 가했고, 디에틸 에테르 및 헥산으로 추출하였다. 유기층을 물, 희석 수성 중탄산나트륨 및 염수로 세척한다음 황산나트륨상에서 건조하여 진공하에서 용매를 제거한 후에 갈색 고형물을 얻었다(81.0g, 87%), 융점 93.5-95.0℃.6-Bromo-2-carboxymethyl-1-hydoxyindane (99.4 g, 367 mmol) was heated with polyphosphoric acid (475 g) for 60 minutes (exothermic bath 70 ° C., exothermic temperature rising to 80 ° C.). ). The reaction was then added to water and extracted with diethyl ether and hexanes. The organic layer was washed with water, dilute aqueous sodium bicarbonate and brine and then dried over sodium sulfate to remove the solvent under vacuum to give a brown solid (81.0 g, 87%), melting point 93.5-95.0 ° C.

1H-NMR(300MHz, CDCl3) 7.64(m,2H), 7.45(dd, 1H, J=8.0, 1.8), 7.37(d, 1H, J=8.0), 3.85(s, 3H), 3.64(d, 2H, J=1.7). 1 H-NMR (300 MHz, CDCl 3 ) 7.64 (m, 2H), 7.45 (dd, 1H, J = 8.0, 1.8), 7.37 (d, 1H, J = 8.0), 3.85 (s, 3H), 3.64 ( d, 2H, J = 1.7).

절차 6Procedure 6

6-브로모-2-인드-(1-엔)오산(7)6-bromo-2-ind- (1-en) oxane (7)

6-브로모-2-카복시메틸-1-인덴(74.3g, 293mmol), 메탄설폰산(19.3ml, 293mmol), 포름산(286ml, 95%) 및 물(15ml)을 6시간동안 환류하에서 기계적으로 교반하였다. 디에틸 에테르, 테트라하이드로푸란 및 물을 가했고, 용액을 매우 희석 용액으로서 추출하였다. 유기층을 물 및 염수로 세척하였다. 활성탄을 5분동안 혼합한다음 규조토를 통해 여과하였다. 황산나트륨상에서 건조하고, 진공하에서 용매를 제거하여 엷은 황색 고형물을 얻었다(62.7g, 89%), 융점 227.5 내지 228.5℃.1H-NMR(300MHz, d6아세톤) 7.81(s, 1H), 7.71(m, 1H), 7.52(s, 2H), 3.67(d,2H, J=2.0).6-Bromo-2-carboxymethyl-1-indene (74.3 g, 293 mmol), methanesulfonic acid (19.3 ml, 293 mmol), formic acid (286 ml, 95%) and water (15 ml) were mechanically refluxed for 6 hours under reflux. Stirred. Diethyl ether, tetrahydrofuran and water were added and the solution was extracted as a very dilute solution. The organic layer was washed with water and brine. Activated carbon was mixed for 5 minutes and then filtered through diatomaceous earth. Dry over sodium sulfate and remove the solvent under vacuum to give a pale yellow solid (62.7 g, 89%), melting point 227.5-228.5 ° C. 1 H-NMR (300 MHz, d 6 acetone) 7.81 (s, 1 H), 7.71 (m, 1 H), 7.52 (s, 2 H), 3.67 (d, 2 H, J = 2.0).

절차 7Procedure 7

(S)-(+)-5-브로모-2-인다노산(8)(S)-(+)-5-bromo-2-indanoic acid (8)

6-브로모-2-인드-(1-엔)오산(29.4g, 123.0mmol), 조생성물[(S)-2,2'-비스(디페닐포스피노)-1,1'-비나프틸]루테늄(II) 디아세테이트(0.67mmol), 탈기체 메탄올(350ml) 및 테트라하이드로푸란(35ml)를 질소(48PSI)하에서 63시간동안 교반하였다. 규조토를 통하여 슬러리를 여과하였고, 용매를 진공하에서 제거하였다. 잔사를 디에틸 에테르와 물사이에서 분배하였다. 유기층을 15% 수성 수산화나트륨으로 염기화하였다. 이 수성층을 농축 염산(0℃)로 산성화하였고, 디에틸 에테르/디클로로메탄으로 추출하였다. 이 유기층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 용매를 진공하에서 제거하여 녹색 고형물을 얻었고, 테트라하이드로푸란 및 페트롤럼 에테르로 분쇄하였다. 액체를 녹색 고형물로부터 따르고, 용매를 진공하에서 제거하여 갈색 고형물을 얻고, 톨루엔 및 페트롤럼 에테르로부터 재결정화하여 갈색 고형물을 수득하였다(23.2g, 78%), 융점 110.0 내지 111.5℃. [α]25 589= +23。(c=0.97MeOH).1H-NMR(300MHz, CDCl3) 7.35(s, 1H), 7.29(d, 1H, J=8.1), 7.08(d, 1H, J=8.0), 3.37(m.1H), 3.24(m,2H), 3.19(m,2H). 카복실산을 알콜(보란 디메틸설파이드 복합체)로 환원시킴으로써 광학적 순도를 측정하고, 1mL/분에서 이소프로판/헥산으로 용출된 키라셀(Chiracel) OD-H 칼럼으로 분석하였다. 재결정되지 않은 조생성물은 95:5비의 에난티오머를 나타낸다. 상기 산은 메탄올 및 디에틸 에테르로부터 (R)-(+)-α-메틸벤질아민염으로서 광학적 순도로 결정화되어 백색 결정을 얻을 수 있었다. 융점 155℃.6-Bromo-2-ind- (1-en) oxane (29.4 g, 123.0 mmol), crude product [(S) -2,2'-bis (diphenylphosphino) -1,1'-binaf Til] ruthenium (II) diacetate (0.67 mmol), outgassing methanol (350 ml) and tetrahydrofuran (35 ml) were stirred under nitrogen (48 PSI) for 63 hours. The slurry was filtered through diatomaceous earth and the solvent was removed in vacuo. The residue was partitioned between diethyl ether and water. The organic layer was basified with 15% aqueous sodium hydroxide. This aqueous layer was acidified with concentrated hydrochloric acid (0 ° C.) and extracted with diethyl ether / dichloromethane. This organic layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo to give a green solid which was triturated with tetrahydrofuran and petroleum ether. The liquid was poured from a green solid and the solvent removed in vacuo to give a brown solid, which was recrystallized from toluene and petroleum ether to give a brown solid (23.2 g, 78%), melting point 110.0 to 111.5 ° C. [a] 25 589 = + 23 ° (c = 0.97 MeOH). 1 H-NMR (300 MHz, CDCl 3 ) 7.35 (s, 1H), 7.29 (d, 1H, J = 8.1), 7.08 (d, 1H, J = 8.0), 3.37 (m.1H), 3.24 (m, 2H), 3.19 (m, 2H). Optical purity was measured by reducing the carboxylic acid with alcohol (borane dimethylsulfide complex) and analyzed on a Chiracel OD-H column eluted with isopropane / hexane at 1 mL / min. Crude product that was not recrystallized showed a 95: 5 ratio of enantiomers. The acid was crystallized in optical purity as (R)-(+)-α-methylbenzylamine salt from methanol and diethyl ether to give white crystals. Melting point 155 캜.

절차 8Procedure 8

(S)-(+)-5-브로모-2-[(2-메틸-(2-프로폭시)카보닐아미노]인단(9)(S)-(+)-5-bromo-2-[(2-methyl- (2-propoxy) carbonylamino] indane (9)

(S)-(+)-5-브로모-2-인다노산(18.9g, 78.4mmol), 디페닐포스포릴 아지드(21.6g, 78.4mmol), t-부탄올(80ml), 1,4-디옥산(80ml) 및 트리에틸아민(10.9ml, 78.4mmol)을 12시간 동안 환류시켰다. 진공하에서 용매를 제거하고, 디에틸 에테르와 물사이에서 잔사를 분배하였다. 유기층을 2N 염산, 수성 중탄산나트륨 및 염수로 세척하였다. 용액을 황산나트륨상에서 건조하였고, 진공하에서 용매를 제거하여 투명한 고형물을 얻었다. 테트라하이드로푸란/헥산(1:10)으로 용출하는 29x5 실리카겔 칼럼상에서 플래쉬 크로마토그래피하였다. 진공하에서 용매를 제거하여 백색 고형물을 얻었다(8.3g, 34%), 융점 125 내지 126℃. [α]25 589= +10。(c=0.95MeOH).(S)-(+)-5-bromo-2-indanoic acid (18.9 g, 78.4 mmol), diphenylphosphoryl azide (21.6 g, 78.4 mmol), t-butanol (80 ml), 1,4- Dioxane (80 ml) and triethylamine (10.9 ml, 78.4 mmol) were refluxed for 12 h. The solvent was removed in vacuo and the residue partitioned between diethyl ether and water. The organic layer was washed with 2N hydrochloric acid, aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate and the solvent was removed in vacuo to yield a clear solid. Flash chromatography on a 29x5 silica gel column eluting with tetrahydrofuran / hexane (1:10). The solvent was removed in vacuo to give a white solid (8.3 g, 34%) with a melting point of 125 to 126 ° C. [a] 25 589 = + 10 ° (c = 0.95 MeOH).

절차 9Procedure 9

(S)-(+)-5-브로모-2-아미노인단(10)(S)-(+)-5-bromo-2-aminoindane (10)

(S)-(+)-5-브로모-2[(2-메틸-(2-프로폭시)카보닐아미노]인단(7.3g, 23.4mmol) 및 트리플루오로아세트산(9ml, 117mmol)을 60분동안 환류시켰다. 진공하에서 트리플루오로아세트산을 제거하였고, 디에틸 에테르/테트라하이드로푸란과 희석 수산화나트륨사이에서 잔사를 분배하였다. 유기층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조시켰다. 용매를 진공하에서 제거하여 투명한 기름을 얻었다(4.9g, 98%). [α]25 589= +17。(c=1.15MeOH).1H-NMR(300MHz, CDCl3) 7.37(s, 1H), 7.27(d, 1H, J=8.2), 7.07(d, 1H, J=7.9), 3.84(m.1H), 3.13(m,2H), 2.64(m,2H), 1.40(s, 2H).(S)-(+)-5-Bromo-2 [(2-methyl- (2-propoxy) carbonylamino] indane (7.3 g, 23.4 mmol) and trifluoroacetic acid (9 ml, 117 mmol) The trifluoroacetic acid was removed under vacuum and the residue was partitioned between diethyl ether / tetrahydrofuran and dilute sodium hydroxide The organic layer was washed with water and brine and dried over sodium sulfate. Removed to give a clear oil (4.9 g, 98%) [α] 25 589 = + 17 ° (c = 1.15MeOH) 1 H-NMR (300 MHz, CDCl 3 ) 7.37 (s, 1H), 7.27 ( d, 1H, J = 8.2), 7.07 (d, 1H, J = 7.9), 3.84 (m. 1H), 3.13 (m, 2H), 2.64 (m, 2H), 1.40 (s, 2H).

절차 10Procedure 10

(S)-(+)-5-브로모-2-N,N-디-1-프로필아미노인단(11)(S)-(+)-5-bromo-2-N, N-di-1-propylaminoindan (11)

(S)-(+)-5-브로모-2-아미노인단(4.8g, 22.6mmol), 1-브로모프로판(10.4ml, 113mmol), 탄산칼륨(6.3g, 45.3mmol) 및 아세토니트릴(50ml)을 22시간동안 환류시켰다. 진공하에서 용매를 제거하였고, 디에틸 에테르와 물사이에서 잔사를 분배하였다. 유기층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 에틸 아세테이트/헥산(3:20)으로 용출하는 24x2cm 실리카겔 칼럼상에서 짙은 기름을 플래쉬 크로마토그래피하였다. 진공하에서 용매를 제거하여 투명한 기름을 수득하였다(5.9g, 88%).(S)-(+)-5-bromo-2-aminoindane (4.8 g, 22.6 mmol), 1-bromopropane (10.4 ml, 113 mmol), potassium carbonate (6.3 g, 45.3 mmol) and acetonitrile ( 50 ml) was refluxed for 22 hours. The solvent was removed in vacuo and the residue was partitioned between diethyl ether and water. The organic layer was washed with water and brine and dried over sodium sulfate. The dark oil was flash chromatographed on a 24 × 2 cm silica gel column eluting with ethyl acetate / hexanes (3:20). Removal of solvent in vacuo gave a clear oil (5.9 g, 88%).

[α]25 589= +7。(c=1.06MeOH).[a] 25 589 = + 7 ° (c = 1.06 MeOH).

메탄올 및 디에틸 에테르로부터 염산염을 결정화하였다. 융점 220.5 내지 221.5℃.Hydrochloride was crystallized from methanol and diethyl ether. Melting point 220.5 to 221.5 ° C.

절차 11Procedure 11

(S)-(+)-5-카복스아미도-2-N,N-디프로필아미노인단(12)(S)-(+)-5-carboxamido-2-N, N-dipropylaminoindane (12)

3급 부틸 리튬(펜탄중에 12.4ml의 1.7M 용액, 21.06mmol)을 -78℃에서 테트라하이드로푸란(20ml)중의 (S)-(+)-5-브로모-2-N,N-디프로필아미노인단(3.1g, 10.53mmol)에 가했다. 7분후에, 트리메틸실일이소시아네이트를 가했고, 냉욕을 제거하였다. 55분후에, 물을 가했고, 상기 혼합물을 디에틸 에테르 및 수성 수산화나트륨으로 추출하였다. 에테르층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하여 엷은 황색 고형물을 얻었다. 융점 97 내지 99℃. [α]25 589= +8。(c=1.00MeOH). 메탄올 및 디에틸 에테르로부터 염산염을 결정화하여 엷은 황색 고형물을 수득하였다(2.19g, 80%), 융점 283 내지 285℃.Tertiary butyl lithium (12.4 ml 1.7 M solution in pentane, 21.06 mmol) in (S)-(+)-5-bromo-2-N, N-dipropyl in tetrahydrofuran (20 ml) at −78 ° C. To amino indan (3.1 g, 10.53 mmol). After 7 minutes, trimethylsilyl isocyanate was added and the cold bath was removed. After 55 minutes, water was added and the mixture was extracted with diethyl ether and aqueous sodium hydroxide. The ether layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo to yield a pale yellow solid. Melting point 97-99 ° C. [a] 25 589 = + 8 ° (c = 1.00 MeOH). Hydrochloride was crystallized from methanol and diethyl ether to give a pale yellow solid (2.19 g, 80%) with a melting point of 283-285 ° C.

절차 12Procedure 12

(S)-(+)-5-하이드록시메틸-2-N,N-디프로필아미노인단(13)(S)-(+)-5-hydroxymethyl-2-N, N-dipropylaminoindan (13)

3급 부틸 리튬(펜탄중에 8.9ml의 1.7M 용액, 15.18mmol)을 -78℃에서 테트라하이드로푸란(12ml)중의 (S)-(+)-5-브로모-2-N,N-디프로필아미노인단(2.25g, 7.59mmol)에 가했다. 5분후에, 상기 반응을 파라포름알데히드(0.27g, 8.36mmol) 및 테트라하이드로푸란(12ml)에 가했다. 60분 후에, 물을 가했고, 상기 혼합물을 디에틸 에테르 및 물로 추출하였다. 에테르층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하여 짙은 갈색 고형물을 얻었고, 디클로로메탄/에틸 아세테이트/헥산(1:4:5) 및 (1:6:3)으로 용출하는 27x2cm 실리카겔 칼럼상에 플래쉬 크로마토그래피하여 화합물(13), 호박색 고형물을 얻었다(1.12g, 60%). 융점 52 내지 54℃.Tertiary butyl lithium (8.9 ml of 1.7 M solution in pentane, 15.18 mmol) in (S)-(+)-5-bromo-2-N, N-dipropyl in tetrahydrofuran (12 ml) at −78 ° C. Amino indan (2.25 g, 7.59 mmol) was added. After 5 minutes, the reaction was added to paraformaldehyde (0.27 g, 8.36 mmol) and tetrahydrofuran (12 ml). After 60 minutes, water was added and the mixture was extracted with diethyl ether and water. The ether layer was washed with water and brine and dried over sodium sulfate. Removal of solvent in vacuo afforded a dark brown solid, flash chromatography on a 27 × 2 cm silica gel column eluting with dichloromethane / ethyl acetate / hexanes (1: 4: 5) and (1: 6: 3) gave compound (13). Obtained an amber solid (1.12 g, 60%). Melting point 52 to 54 ° C.

절차 13Procedure 13

(S)-(+)-5-아미노메틸-2-N,N-디-1-프로필아미노인단(14)(S)-(+)-5-aminomethyl-2-N, N-di-1-propylaminoindan (14)

아미드(13)(1.8g, 6.9mMol)을 THF(20ml)중에서 용해하였고, 보란-메틸설파이드(2.7ml의 10M 용액)을 가했다. 이 용액을 1시간동안 환류로 가열한다음 냉각시켰다. 수성 2N 염산(20ml)을 조심스럽게 가했고, 상기 용액을 2시간동안 교반하였다. 2N 수산화나트륨으로 중화후에, 상기 용액을 에테르로 추출하였다. 에테르 층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 용매를 제거하여 기름으로서 아민을 산출하였다.Amide 13 (1.8 g, 6.9 mMol) was dissolved in THF (20 ml) and borane-methylsulfide (2.7 ml of 10 M solution) was added. The solution was heated to reflux for 1 hour and then cooled. Aqueous 2N hydrochloric acid (20 ml) was added carefully and the solution was stirred for 2 hours. After neutralization with 2N sodium hydroxide, the solution was extracted with ether. The ether layer was washed with water and brine and dried over sodium sulfate. Solvent was removed to yield amine as oil.

절차 14Procedure 14

(S)-(+)-5-메틸설폭시메틸-2-N,N-디프로필아미노인단(15)(S)-(+)-5-methylsulfoxymethyl-2-N, N-dipropylaminoindan (15)

메탄설포닐 클로라이드(0.37ml, 4.67mmol), 화합물(13)(1.05g, 4.24mmol), 트리에틸아민(0.71ml, 5.09mmol) 및 디클로로메탄(10ml)을 0℃에서 교반했다. 2시간후에, 상기 혼합물을 디에틸 에테르 및 수성 중탄산나트륨으로 추출하였다. 에테르 층을 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하여 호박색 기름을 얻었다(1.2g, 87% 조생성물).Methanesulfonyl chloride (0.37 ml, 4.67 mmol), compound (13) (1.05 g, 4.24 mmol), triethylamine (0.71 ml, 5.09 mmol) and dichloromethane (10 ml) were stirred at 0 ° C. After 2 hours, the mixture was extracted with diethyl ether and aqueous sodium bicarbonate. The ether layer was washed with brine and dried over sodium sulfate. Removal of solvent in vacuo afforded amber oil (1.2 g, 87% crude product).

절차 15Procedure 15

(S)-(+)-5-페닐설포닐메틸-2-N,N-디프로필아미노인단(16)(S)-(+)-5-phenylsulfonylmethyl-2-N, N-dipropylaminoindan (16)

벤젠설핀산, 나트륨염(0.54g, 3.23mmol), 화합물(15)(0.35g, 1.08mmol) 및 디메틸포름아미드(5ml)를 50℃에서 교반하였다. 24시간후에, 상기 혼합물을 디에틸 에테르 및 수성 중탄산나트륨으로 추출하였다. 에테르층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하여 짙은 기름을 얻었고, 디클로로메탄/에틸 아세테이트/헥산(1:6:13)으로 용출하는 22x1cm 실리카겔 칼럼상에 플래쉬 크로마토그래피하였다. 설폰(16)을 엷은 기름으로 얻었다(0.12g, 30%).Benzenesulfinic acid, sodium salt (0.54 g, 3.23 mmol), compound (15) (0.35 g, 1.08 mmol) and dimethylformamide (5 ml) were stirred at 50 ° C. After 24 hours, the mixture was extracted with diethyl ether and aqueous sodium bicarbonate. The ether layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo to give a dark oil which was flash chromatographed on a 22 × 1 cm silica gel column eluting with dichloromethane / ethyl acetate / hexanes (1: 6: 13). Sulfon (16) was obtained as a light oil (0.12 g, 30%).

절차 16Procedure 16

(S)-(+)-5-카복스아미도메틸-2-N,N-디프로필아미노인단(17)(S)-(+)-5-carboxamidomethyl-2-N, N-dipropylaminoindan (17)

시안화나트륨(0.51g, 9.83mmol), 화합물(15)(0.80g, 2.46mmol) 및 디메틸포름아미드(5ml)를 50℃에서 교반하였다. 24시간 후에, 상기 혼합물을 디에틸 에테르, 디클로로메탄 및 수성 중탄산나트륨으로 추출하였다. 에테르 층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하여 짙은 기름을 얻었고, 디클로로메탄/에틸 아세테이트/헥산(1:3:16), (1:6:15) 및 (1:10:9)로 용출하는 21x2cm 실리카겔 칼럼상에 플래쉬 크로마토그래피하였다. 진공하에서 용매를 제거하여 짙은 기름으로서 시아노메틸 첨가물을 수득하였다(0.35g, 55%). 이 기름을 15% 수성 수산화나트륨(2.1ml), 테트라하이드로푸란(12ml) 및 30% 과산화수소(13.7ml)와 혼합하였다. 54시간 후에, 디에틸 에테르 및 물을 가했고, 생성물을 추출하였다. 에테르 층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하여 백색 왁스를 얻었다(0.19g, 59%).Sodium cyanide (0.51 g, 9.83 mmol), compound (15) (0.80 g, 2.46 mmol) and dimethylformamide (5 ml) were stirred at 50 ° C. After 24 hours, the mixture was extracted with diethyl ether, dichloromethane and aqueous sodium bicarbonate. The ether layer was washed with water and brine and dried over sodium sulfate. Removal of solvent in vacuo gave a dark oil which was flashed on a 21 × 2 cm silica gel column eluting with dichloromethane / ethyl acetate / hexanes (1: 3: 16), (1: 6: 15) and (1: 10: 9). Chromatography. The solvent was removed in vacuo to give the cyanomethyl additive as a dark oil (0.35 g, 55%). This oil was mixed with 15% aqueous sodium hydroxide (2.1 ml), tetrahydrofuran (12 ml) and 30% hydrogen peroxide (13.7 ml). After 54 hours, diethyl ether and water were added and the product extracted. The ether layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo to yield a white wax (0.19 g, 59%).

절차 17Procedure 17

(R)-(-)-5-클로로메틸-2-N,N-디프로필아미노인단(18)(R)-(-)-5-chloromethyl-2-N, N-dipropylaminoindan (18)

티오닐 클로라이드(2.3ml)를 냉욕중의 (R)-(-)-5-하이드록시메틸-2-N,N-디프로필아미노인단(건조 THF의 60ml중의 7.5g)에 천천히 가했다. 실온에서 60분후에, 에탄올(5ml)을 가했고, 환류시켜 가열하였다. 진공하에서 용매를 제거하고, 수성 수산화나트륨을 잔사에 가했다. 에테르로 추출하였다. 에테르 층을 물 및 염수로 세척한다음 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하였고, 잔사를 플래쉬 크로마토그래피하였다; 에틸 아세테이트/디클로로메탄/헥산으로 용출하여 기름을 수득하였다.Thionyl chloride (2.3 ml) was slowly added to (R)-(-)-5-hydroxymethyl-2-N, N-dipropylaminoindan (7.5 g in 60 ml of dry THF) in a cold bath. After 60 minutes at room temperature, ethanol (5 ml) was added and heated to reflux. The solvent was removed under vacuum and aqueous sodium hydroxide was added to the residue. Extract with ether. The ether layer was washed with water and brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was flash chromatographed; Elution with ethyl acetate / dichloromethane / hexanes gave an oil.

절차 18Procedure 18

(R)-(-)-5-(4-브로모벤젠)티오메틸-2-N,N-디프로필아미노인단(19)(R)-(-)-5- (4-bromobenzene) thiomethyl-2-N, N-dipropylaminoindan (19)

(R)-(-)-5-클로로메틸-2-N,N-디프로필아미노인단(3.0g), 4-브로모티오페놀(2.4g), 수산화나트륨(2N 수용액의 28ml), 테트라하이드로푸란(28ml) 및 테트라부틸암모늄 클로라이드의 촉매량을 50℃에서 60분동안 가열하였다. 물을 가했고, 혼합물을 에테르로 추출하였다. 에테르 층을 물 및 2N 염산으로 세척하였다. 산층을 수성 수산화나트륨으로 염기화하였고, 에테르/디클로로메탄으로 추출하였다. 유기층을 물 및 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하였고, 잔사를 플래쉬 크로마토그래피하였다; 에틸 아세테이트/디클로로메탄/헥산으로 용출하여 고형물을 수득하였다. 융점 80 내지 82℃. 메탄올/에테르로부터 재결정화된 염산염을 고형물로 얻었다. 융점 142 내지 144℃.(R)-(-)-5-chloromethyl-2-N, N-dipropylaminoindane (3.0 g), 4-bromothiophenol (2.4 g), sodium hydroxide (28 ml of 2N aqueous solution), tetrahydro The catalytic amount of furan (28 ml) and tetrabutylammonium chloride was heated at 50 ° C. for 60 minutes. Water was added and the mixture was extracted with ether. The ether layer was washed with water and 2N hydrochloric acid. The acid layer was basified with aqueous sodium hydroxide and extracted with ether / dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was flash chromatographed; Elution with ethyl acetate / dichloromethane / hexanes gave a solid. Melting point 80-82 ° C. Hydrochloride recrystallized from methanol / ether was obtained as a solid. Melting point 142 to 144 ° C.

절차 19Procedure 19

(R)-(-)-5-(4-브로모벤젠)설포닐메틸-2-N,N-디프로필아미노인단(20)(R)-(-)-5- (4-bromobenzene) sulfonylmethyl-2-N, N-dipropylaminoindane (20)

냉수욕중에서 빙초산(7.5ml)중의 (R)-(-)-5-(4-브로모벤젠)티오메틸-2-N,N-디프로필아미노인단(1.5g)에 과초산(1.7ml, 아세트산/물중에 32%)을 가했다. 4시간후에, 메틸 설파이드(1ml)를 가했고; 추가의 30분후에, 수산화암모늄(3M)을 가했고 혼합물을 에테르로 추출하였다. 에테르층을 물 및 염수로 세척한다음 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하여 고형물을 수득하였다. 융점 132 내지 134℃. 메탄올/에테르로부터 재결정화된 말레이트 염을 고형물로 얻었다. 융점 130 내지 131℃.Peracetic acid (1.7 ml, acetic acid) in (R)-(-)-5- (4-bromobenzene) thiomethyl-2-N, N-dipropylaminoindan (1.5 g) in glacial acetic acid (7.5 ml) in a cold water bath. / 32% in water). After 4 hours methyl sulfide (1 ml) was added; After another 30 minutes, ammonium hydroxide (3M) was added and the mixture was extracted with ether. The ether layer was washed with water and brine and then dried over sodium sulfate. The solvent was removed in vacuo to give a solid. Melting point 132 to 134 ° C. A maleate salt recrystallized from methanol / ether was obtained as a solid. Melting point 130 to 131 ° C.

절차 20Procedure 20

(R)-(-)-5-(4-카복스아미도벤젠)설포닐메틸-2-N,N-디프로필아미노인단(21)(R)-(-)-5- (4-carboxamidobenzene) sulfonylmethyl-2-N, N-dipropylaminoindan (21)

(R)-(-)-5-(4-브로모벤젠)설포닐메틸-2-N,N-디프로필아미노인단(0.94g), 팔라듐 아세테이트(0.05g), 1,3-비스(디페닐포스피노)프로판(0.21g), 디이소프로필에틸아민(0.75ml), 디메틸포름아미드(5ml) 및 포름아미드(0.42ml)를 120℃에서 일산화탄소하에서 가열하였다. 7시간 후에, 실온으로 냉각하였고, 수산화나트륨을 가했다(5ml, 2N). 물을 가했고, 혼합물을 에테르/테트라하이드로푸란으로 추출하였다. 에테르 층을 물 및 염수로 세척한다음 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하였고, 잔사를 플래쉬 크로마토그래피하였다; 메탄올/디클로로메탄으로 용출하여 고형물을 수득하였다. 융점 164 내지 165℃. 메탄올/에테르로부터 재결정화된 푸마레이트 염을 고형물로 얻었다. 융점 159 내지 163℃.(R)-(-)-5- (4-bromobenzene) sulfonylmethyl-2-N, N-dipropylaminoindan (0.94 g), palladium acetate (0.05 g), 1,3-bis (di Phenylphosphino) propane (0.21 g), diisopropylethylamine (0.75 ml), dimethylformamide (5 ml) and formamide (0.42 ml) were heated at 120 ° C. under carbon monoxide. After 7 hours, cooled to room temperature and sodium hydroxide was added (5 ml, 2N). Water was added and the mixture was extracted with ether / tetrahydrofuran. The ether layer was washed with water and brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was flash chromatographed; Elution with methanol / dichloromethane gave a solid. Melting point 164-165 캜. Fumarate salt recrystallized from methanol / ether was obtained as a solid. Melting point 159 to 163 ° C.

절차 21Procedure 21

(R)-(-)-5-(4-시아노벤젠)설포닐메틸-2-N,N-디프로필아미노인단(22)(R)-(-)-5- (4-cyanobenzene) sulfonylmethyl-2-N, N-dipropylaminoindane (22)

티타늄 테트라클로라이드(사염화탄소중의 0.15ml, 3ml)를 냉욕중의 (R)-(-)-5-(4-카복스아미도벤젠)설포닐메틸-2-N,N-디프로필아미노인단(0.23g), 트리에틸아민(0.46ml) 및 테트라하이드로푸란(5ml)에 가했다. 16.5시간후에, 수성 탄산나트륨을 가했고, 혼합물을 에테르로 추출하였다. 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하였고, 잔사를 플래쉬 크로마토그래피하였다; 에틸 아세테이트/디클로로메탄/헥산으로 용출하여 고형물을 수득하였다. 에틸 아세테이트/헥산으로부터 재결정화된 분석적 시료를 고형물로 얻었다. 융점 90 내지 91℃. 메탄올/에테르로부터 재결정화된 염산염을 고형물로 얻었다. 융점 175℃(분해).Titanium tetrachloride (0.15 ml in carbon tetrachloride, 3 ml) was subjected to (R)-(-)-5- (4-carboxamidobenzene) sulfonylmethyl-2-N, N-dipropylaminoindan in a cold bath ( 0.23 g), triethylamine (0.46 ml) and tetrahydrofuran (5 ml). After 16.5 hours, aqueous sodium carbonate was added and the mixture was extracted with ether. Washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was flash chromatographed; Elution with ethyl acetate / dichloromethane / hexanes gave a solid. Analytical samples recrystallized from ethyl acetate / hexanes were obtained as a solid. Melting point 90-91 degreeC. Hydrochloride recrystallized from methanol / ether was obtained as a solid. Melting point 175 ° C. (decomposition).

절차 22Procedure 22

(R)-(-)-5-아미노-2-N,N-디프로필아미노인단(23)(R)-(-)-5-amino-2-N, N-dipropylaminoindan (23)

t-부틸리튬(9.9ml, 펜탄중의 1.7M)을 -78℃에서 테트라하이드로푸란(15ml)중의 (R)-(-)-5-브로모-2-N,N-디프로필아미노인단(11)(2.5g)에 가했다. 5분후에, 디페닐포스포릴 아지드(2.0ml)를 가했고, 반응용기로부터 빛을 차단하였다. 냉욕을 제거하였고, 45분후에 다시 적용하였다. 리튬 알루미늄 하이드라이드(42ml, 테트라하이드로푸란중의 1.0N)를 가했고, 반응을 실온으로 승온시켰다. 수성 염산을 가했고, 혼합물을 에테르/테트라하이드로푸란으로 추출하였다. 산층을 15% 수산화나트륨으로 염기화하였고, 에테르/테트라하이드로푸란으로 추출하였다. 유기층을 염수로 세척하였고, 규조토를 통해 여과하고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하였고, 잔사를 플래쉬 크로마토그래피하였다; 메탄올/디클로로메탄으로 용출하여 기름을 수득하였다.t-butyllithium (9.9 ml, 1.7 M in pentane) was dissolved in (R)-(-)-5-bromo-2-N, N-dipropylaminoindan in tetrahydrofuran (15 ml) at -78 ° C. 11) (2.5 g). After 5 minutes, diphenylphosphoryl azide (2.0 ml) was added and light was blocked from the reaction vessel. The cold bath was removed and reapplied after 45 minutes. Lithium aluminum hydride (42 ml, 1.0 N in tetrahydrofuran) was added and the reaction was allowed to warm to room temperature. Aqueous hydrochloric acid was added and the mixture was extracted with ether / tetrahydrofuran. The acid layer was basified with 15% sodium hydroxide and extracted with ether / tetrahydrofuran. The organic layer was washed with brine, filtered through diatomaceous earth and dried over sodium sulfate. The solvent was removed in vacuo and the residue was flash chromatographed; Elution with methanol / dichloromethane gave oil.

절차 23Procedure 23

(R)-(-)-5-벤젠설폰아미도-2-N,N-디프로필아미노인단(24)(R)-(-)-5-benzenesulfonamido-2-N, N-dipropylaminoindan (24)

벤젠설포닐 클로라이드(0.45ml)를 (R)-(-)-5-아미노-2-N,N-디프로필아미노인단(0.4g), 트리에틸아민(0.48ml) 및 디클로로메탄(5ml)에 가했다. 19시간후에, 수산화암모늄(3M 수성)을 가했고, 혼합물을 에테르로 추출하였다. 에테르 층을 염수로 세척하였고, 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하였고, 잔사를 플래쉬 크로마토그래피하였다; 에틸 아세테이트/디클로로메탄/헥산으로 용출하여 0.51g의 디페닐설폰아미도 부가물을 수득하였다. 메탄올(5ml) 및 물(0.5ml)중에 수산화칼륨(0.19g)을 가했다. 17시간후에, 진공하에서 용매를 제거하였고, 염산(2N 수성)을 가한다음 수성 중탄산나트륨으로 염기화하였다. 혼합물을 에테르/디클로로메탄으로 추출하였고, 염수로 세척한다음 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하여 기름을 수득하였다. 메탄올/에테르로부터 재결정화된 염산염은 고형물였다. 융점 214 내지 215℃.Benzenesulfonyl chloride (0.45 ml) was added to (R)-(-)-5-amino-2-N, N-dipropylaminoindan (0.4 g), triethylamine (0.48 ml) and dichloromethane (5 ml). Added. After 19 hours, ammonium hydroxide (3M aqueous) was added and the mixture was extracted with ether. The ether layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was flash chromatographed; Elution with ethyl acetate / dichloromethane / hexanes gave 0.51 g of diphenylsulfonamido adduct. Potassium hydroxide (0.19 g) was added in methanol (5 ml) and water (0.5 ml). After 17 hours, the solvent was removed in vacuo, hydrochloric acid (2N aqueous) was added and then basified with aqueous sodium bicarbonate. The mixture was extracted with ether / dichloromethane, washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to yield an oil. Hydrochloride recrystallized from methanol / ether was a solid. Melting point 214-215 degreeC.

(R)-(-)-5-(4-클로로벤젠)설폰아미도-2-N,N-디프로필아미노인단(25)(R)-(-)-5- (4-chlorobenzene) sulfonamido-2-N, N-dipropylaminoindane (25)

벤젠설포닐 클로라이드대신 4-클로로벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노-2-N,N-디프로필아미노인단을 절차 23에 따라 처리하여 표제 화합물을 기름으로 수득하였다. 메탄올/에테르로부터 재결정화된 말레산 염을 고형물로 얻었다. 융점 167 내지 169℃.Using 4-chlorobenzenesulfonyl chloride instead of benzenesulfonyl chloride and treating (R)-(-)-5-amino-2-N, N-dipropylaminoindan according to procedure 23 to give the title compound as an oil. Obtained. Maleic acid salt recrystallized from methanol / ether was obtained as a solid. Melting point 167-169 degreeC.

절차 24Procedure 24

(R)-(-)-5-에탄설폰아미도메틸-2-N,N-디프로필아미노인단(26)(R)-(-)-5-ethanesulfonamidomethyl-2-N, N-dipropylaminoindan (26)

에탄설포닐 클로라이드(0.2ml)를 (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단(14)(0.5g), 피리딘(0.3ml) 및 테트라하이드로푸란(5ml)에 가했다. 2.5시간후에, 수산화암모늄을 가했고, 혼합물을 에테르로 추출하였다. 에테르 층을 물 및 염수로 세척한다음 황산나트륨상에서 건조하였다. 진공하에서 용매를 제거하였고, 잔사를 플래쉬 크로마토그래피하였다; 에틸 아세테이트/디클로로메탄/헥산으로 용출하여 기름을 수득하였다. 메탄올/에테르로부터 재결정화된 푸마레이트 염을 고형물로 얻었다. 융점 129 내지 130℃.Ethanesulfonyl chloride (0.2 ml) was added to (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan (14) (0.5 g), pyridine (0.3 ml) and tetrahydrofuran ( 5 ml). After 2.5 hours, ammonium hydroxide was added and the mixture was extracted with ether. The ether layer was washed with water and brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was flash chromatographed; Elution with ethyl acetate / dichloromethane / hexanes gave an oil. Fumarate salt recrystallized from methanol / ether was obtained as a solid. Melting point 129-130 ° C.

(R)-(-)-5-벤젠설폰아미도메틸-2-N,N-디프로필아미노인단(27)(R)-(-)-5-benzenesulfonamidomethyl-2-N, N-dipropylaminoindan (27)

에탄설포닐 클로라이드대신 벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 기름으로 수득하였다. 메탄올/에테르로부터 재결정화된 말레이트 염을 고형물로 얻었다. 융점 144 내지 145℃.(R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan was treated according to Procedure 24 using benzenesulfonyl chloride instead of ethanesulfonyl chloride to give the title compound as an oil. . A maleate salt recrystallized from methanol / ether was obtained as a solid. Melting point 144 to 145 ° C.

(R)-(-)-5-(4-클로로벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(28)(R)-(-)-5- (4-chlorobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindane (28)

에탄설포닐 클로라이드대신 4-클로로벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 융점 84 내지 87℃.Using the 4-chlorobenzenesulfonyl chloride instead of ethanesulfonyl chloride and treating (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan according to procedure 24 to give the title compound as a solid. Obtained. Melting point 84-87 ° C.

(R)-(-)-5-(3,4-디클로로벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(29)(R)-(-)-5- (3,4-dichlorobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan (29)

에탄설포닐 클로라이드대신 3,4-디클로로벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 톨루엔/헥산으로부터 재결정화하여 고형물을 얻었다. 융점 87 내지 90℃.(R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan was treated according to Procedure 24 using 3,4-dichlorobenzenesulfonyl chloride instead of ethanesulfonyl chloride to give the title compound Was obtained as a solid. Recrystallization from toluene / hexanes gave a solid. Melting point 87-90 ° C.

(R)-(-)-5-(4-요오도벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(30)(R)-(-)-5- (4-iodobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindane (30)

에탄설포닐 클로라이드대신 4-요오도벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 에테르/헥산으로부터 재결정화는 고형물을 얻었다. 융점 77 내지 78℃.Using 4-iodobenzenesulfonyl chloride instead of ethanesulfonyl chloride, (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan was treated according to Procedure 24 to give the title compound. Obtained as a solid. Recrystallization from ether / hexanes gave a solid. Melting point 77-78 ° C.

(R)-(-)-5-(4-아세트아미도벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(31)(R)-(-)-5- (4-acetamidobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan (31)

에탄설포닐 클로라이드대신 4-아세트아미도벤젠설포닐 클로라이드를 사용하여, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 이소프로판올로부터 재결정화된 염산염을 고형물로 얻었다. 융점 217 내지 218℃.(R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan was treated according to Procedure 24 using 4-acetamidobenzenesulfonyl chloride instead of ethanesulfonyl chloride to give the title compound Was obtained as a solid. Hydrochloride recrystallized from isopropanol was obtained as a solid. Melting point 217-218 ° C.

(R)-(-)-5-(4-아세트아미도-3-클로로벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(32)(R)-(-)-5- (4-acetamido-3-chlorobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindane (32)

에탄설포닐 클로라이드대신 4-아세트아미도-3-클로로벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 융점 58 내지 60℃.Use 4-acetamido-3-chlorobenzenesulfonyl chloride instead of ethanesulfonyl chloride and (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindane according to procedure 24 Treatment gave the title compound as a solid. Melting point 58 to 60 ° C.

(R)-(-)-5-(4-트리플루오로메틸벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(33)(R)-(-)-5- (4-trifluoromethylbenzene) sulfonamidomethyl-2-N, N-dipropylaminoindane (33)

에탄설포닐 클로라이드대신 4-트리플루오로벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 기름으로 수득하였다. 융점 66 내지 70℃.The title compound was treated by using 4-trifluorobenzenesulfonyl chloride instead of ethanesulfonyl chloride and (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindane according to Procedure 24 Was obtained as oil. Melting point 66-70 ° C.

(R)-(-)-5-(4-니트로벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(34)(R)-(-)-5- (4-nitrobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindane (34)

에탄설포닐 클로라이드대신 4-니트로벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 융점 94 내지 97℃. 에테르로 분쇄된 염산염을 고형물로 얻었다.Using the 4-nitrobenzenesulfonyl chloride instead of ethanesulfonyl chloride and treating (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan according to procedure 24 to give the title compound as a solid. Obtained. Melting point 94-97 ° C. Hydrochloride triturated with ether was obtained as a solid.

(R)-(-)-5-(4-시아노벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(35)(R)-(-)-5- (4-cyanobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindane (35)

에탄설포닐 클로라이드대신 4-시아노벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 융점 104 내지 106℃. 메탄올/에테르로부터 재결정화된 푸마레이트 염을 고형물로 얻었다. 융점 174 내지 177℃.Using 4-cyanobenzenesulfonyl chloride instead of ethanesulfonyl chloride and treating (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan according to procedure 24 to give the title compound Obtained as a solid. Melting point 104 to 106 ° C. Fumarate salt recrystallized from methanol / ether was obtained as a solid. Melting point 174-177 ° C.

(R)-(-)-5-(3-시아노벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(36)(R)-(-)-5- (3-cyanobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindane (36)

에탄설포닐 클로라이드대신 3-시아노벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 기름으로 수득하였다. 에테르로 분쇄된 염산염을 고형물로 얻었다. 융점 110℃(분해).Using the 3-cyanobenzenesulfonyl chloride instead of ethanesulfonyl chloride, (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan was treated according to procedure 24 to obtain the title compound. Obtained as oil. Hydrochloride triturated with ether was obtained as a solid. Melting point 110 ° C. (decomposition).

(R)-(-)-5-(2-시아노벤젠)설폰아미도메틸-2-N,N-디프로필아미노인단(37)(R)-(-)-5- (2-cyanobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindane (37)

에탄설포닐 클로라이드대신 2-시아노벤젠설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 메탄올/에테르로부터 재결정화된 염산염을 고형물로 얻었다. 융점 185℃(분해).Using the 2-cyanobenzenesulfonyl chloride instead of ethanesulfonyl chloride and treating (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan according to procedure 24 to give the title compound Obtained as a solid. Hydrochloride recrystallized from methanol / ether was obtained as a solid. Melting point 185 ° C. (decomposition).

(R)-(-)-5-[2-(5-트리플루오로)피리딘]설폰아미도메틸-2-N,N-디프로필아미노인단 (38)(R)-(-)-5- [2- (5-trifluoro) pyridine] sulfonamidomethyl-2-N, N-dipropylaminoindane (38)

에탄설포닐 클로라이드대신 2-(5-트리플루오로)피리딘설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 고형물로 수득하였다. 융점 125 내지 127℃. 메탄올/에테르로부터 재결정화된 염산염을 고형물로 얻었다. 융점 207 내지 209℃.Use 2- (5-trifluoro) pyridinesulfonyl chloride instead of ethanesulfonyl chloride and (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan according to procedure 24 Treatment gave the title compound as a solid. Melting point 125-127 ° C. Hydrochloride recrystallized from methanol / ether was obtained as a solid. Melting point 207-209 캜.

(R)-(-)-5-[3-(2,5-디클로로)티오페닐]설폰아미도메틸-2-N,N-디프로필아미노인단 (39)(R)-(-)-5- [3- (2,5-dichloro) thiophenyl] sulfonamidomethyl-2-N, N-dipropylaminoindane (39)

에탄설포닐 클로라이드대신 2,5-디클로로티오펜-3-설포닐 클로라이드를 사용하고, (R)-(-)-5-아미노메틸-2-N,N-디프로필아미노인단을 절차 24에 따라 처리하여 표제 화합물을 투명한 기름으로 수득하였다. 에테르/헥산으로부터 결정화로 고형물을 얻었다. 융점 79 내지 80℃. 메탄올/에테르로부터 재결정화된 염산염을 고형물로 얻었다. 융점 106℃(분해).Use 2,5-dichlorothiophene-3-sulfonyl chloride instead of ethanesulfonyl chloride and (R)-(-)-5-aminomethyl-2-N, N-dipropylaminoindan according to procedure 24 Treatment gave the title compound as a clear oil. Crystallization from ether / hexane gave a solid. Melting point 79 to 80 ° C. Hydrochloride recrystallized from methanol / ether was obtained as a solid. Melting point 106 ° C. (decomposition).

절차 25Procedure 25

디메틸 2,2-디(2-프로피닐)말로네이트(40)Dimethyl 2,2-di (2-propynyl) malonate (40)

수성 수산화나트륨(12N 용액의 1500ml)을 수성 수산화나트륨(12N 용액의 1500ml)을 상부 교반기가 구비된 플라스크에 넣었다. 벤지트리에틸암모늄 클로라이드(54g)를 가했고, 용액을 0℃로 냉각시켰다. 디메틸말로네이트(79.3g) 및 프로파길 브로마이드(3당량, 214g)의 용액을 격렬하게 교반하면서 25분동안 부가 깔대기로 가하였고, 온도를 25℃이하로 유지하였다(R.K. Singh, Synthesis 1985, 54). 다음으로 슬러리를 3시간동안 25℃에서 교반하였다. 다음으로 슬러리를 냉욕에서 냉각시킨 다음 조심스럽게 얼음/물 혼합물에 가했다. t-부틸 메틸 에테르로 추출하였고, 물(2X)로 유기층을 세척한다음 염수로 세척하였다. 황산나트륨상에서 건조하였고, 용매를 제거하여 표제 화합물을 결정성 고형물(92% 수율)로서 얻었다.Aqueous sodium hydroxide (1500 ml of 12N solution) and aqueous sodium hydroxide (1500 ml of 12N solution) were placed in a flask equipped with an upper stirrer. Benzitriethylammonium chloride (54 g) was added and the solution was cooled to 0 ° C. A solution of dimethylmalonate (79.3 g) and propargyl bromide (3 equiv, 214 g) was added to the addition funnel for 25 minutes with vigorous stirring and the temperature was kept below 25 ° C (RK Singh, Synthesis 1985, 54). . The slurry was then stirred at 25 ° C. for 3 hours. The slurry was then cooled in a cold bath and then carefully added to the ice / water mixture. Extracted with t-butyl methyl ether, washed the organic layer with water (2X) and then brine. Dry over sodium sulfate and remove the solvent to afford the title compound as a crystalline solid (92% yield).

절차 26Procedure 26

메틸 2-(2-프로피닐)-4-펜티노에이트(41)Methyl 2- (2-propynyl) -4-pentinoate (41)

디메틸설폭시드(341ml)중의 염화나트륨(25g) 및 물(23ml)로 170℃에서 가열함으로써 디메틸 2,2-디(2-프로피닐)말로네이트(71g)을 크라프초(Krapcho) 탈카복실화로 처리하였다. 15시간 후에, 상기 용액을 냉각시키고, 물 및 t-부틸 메틸 에테르로 희석하고 추출하였다. 유기층을 물(4X) 및 염수로 세척한다음 황산나트륨상에서 건조하였다. 용매를 제거하여 액체를 수득한후 증류하고, 109℃에서 표제 화합물을 수집하였다(28mm Hg).Dimethyl 2,2-di (2-propynyl) malonate (71 g) was treated by Krapcho decarboxylation by heating at 170 ° C. with sodium chloride (25 g) and water (23 ml) in dimethyl sulfoxide (341 ml). . After 15 hours, the solution was cooled, diluted with water and t-butyl methyl ether and extracted. The organic layer was washed with water (4X) and brine and then dried over sodium sulfate. The solvent was removed to give a liquid which was distilled off and the title compound was collected at 109 ° C. (28 mm Hg).

절차 27Procedure 27

2-(2-프로피닐)-4-펜티노산(42)2- (2-propynyl) -4-pentinoic acid (42)

메틸 2-(2-프로피닐)-4-펜티노에이트(27.5g)를 환류수(250ml)중의 수산화나트륨(22g)으로 비누화하였다. 용액을 냉각하였고, 12N HCl로 pH 3으로 산성화한다음 t-부틸 메틸 에테르로 추출하였다. 유기층을 염수로 세척하였고, 황산나트륨상에서 건조하였다. 용매를 제거하여 표제 화합물을 수득하였다.Methyl 2- (2-propynyl) -4-pentinoate (27.5 g) was saponified with sodium hydroxide (22 g) in reflux (250 ml). The solution was cooled, acidified to pH 3 with 12N HCl and extracted with t-butyl methyl ether. The organic layer was washed with brine and dried over sodium sulfate. Removal of solvent gave the title compound.

절차 28Procedure 28

4-(t-부틸옥시카보닐아미노)헵타-1,6-디인(43)4- (t-butyloxycarbonylamino) hepta-1,6-diyne (43)

톨루엔중의 2-(2-프로피닐)-4-펜티노산 42(25.0g, 0.184mol)에 트리에틸아민(19.5g, 0.193mol)을 냉각시키면서 가했다. 디페닐포스포릴 아지드(50.5g, 0.184mol)을 가했고, 혼합물을 실온에서 15분동안 교반하였다. 반응이 발열성이 될때까지 상기 혼합물을 증기욕에서 가열하였다. 반응이 진정되고, 기체의 방출이 중단되는동안 추가의 10분동안 가열을 계속하였다. 건조 t-부탄올(150ml)을 가했고, 상기 혼합물을 24시간동안 증기욕의 환류에서 가열하였다. 진공하에서 용매를 제거하고, 잔사를 물로 희석하였고, 디에틸에테르로 2회 추출하였다. 혼합 수성 추출물을 물(2회), 10% 탄산나트륨 용액 및 염수로 세척하였다. 용액을 건조시켰고(MgSO4), 용매를 진공하에서 제거하여 적갈색 고형물(35.35g)로서 조생성물(43)을 얻었다. 시료(3.2g)를 플래쉬 크로마토그래피(230 내지 400메쉬 실리카겔, 헥산중의 10% 에틸 아세테이트)를 통해 정제하여 무색 고형물(2.69g)를 얻었다. 헥산으로부터 결정은 무색 결정으로서 표제 화합물(43)을 얻었다(융점. 64 내지 67℃).Triethylamine (19.5 g, 0.193 mol) was added to 2- (2-propynyl) -4-pentinoic acid 42 (25.0 g, 0.184 mol) in toluene while cooling. Diphenylphosphoryl azide (50.5 g, 0.184 mol) was added and the mixture was stirred at room temperature for 15 minutes. The mixture was heated in a steam bath until the reaction was exothermic. The heating was continued for an additional 10 minutes while the reaction was calm and the release of gas was stopped. Dry t-butanol (150 ml) was added and the mixture was heated at reflux in a steam bath for 24 h. The solvent was removed in vacuo, the residue was diluted with water and extracted twice with diethyl ether. The combined aqueous extracts were washed with water (twice), 10% sodium carbonate solution and brine. The solution was dried (MgSO 4 ) and the solvent removed under vacuum to afford crude product 43 as a reddish brown solid (35.35 g). Sample (3.2 g) was purified via flash chromatography (230-400 mesh silica gel, 10% ethyl acetate in hexane) to give a colorless solid (2.69 g). Crystals from hexane obtained the title compound (43) as colorless crystals (melting point, 64 to 67 ° C).

절차 29Procedure 29

4-아미노헵타-1,6-디인(44)4-aminohepta-1,6-diyne (44)

4-(t-부틸옥시카보닐아미노)헵타-1,6-디인(43)(30.28g, 0.146mol)을 얼음중에서 냉각시키고, 트리플루오로아세트산(90ml)을 교반하면서 가했다. 혼합물을 20분동안 교반하였고, 과량의 트리플루오로아세트산을 진공하에서 제거하였다. 혼합물을 물 및 디에틸에테르로 분배하였고, 에테르 용액을 5% 염산 용액으로 2회 추출하였다. 혼합된 수성 추출물을 얼음중에서 냉각된 디에틸에테르로 세척하였고, 고형물 수산화나트륨으로 염기성화하였다. 상기 혼합물을 염화나트륨으로 포화하였고, 디에틸에테르로 3회 추출하였다. 혼합된 추출물을 염수 및 건조(MgSO4)하였다. 진공하에서 용매를 제거하여 호박색 기름(13.2g, 84%)으로서 표제 화합물(44)을 얻었다. 시료(0.526g)를 푸마르산(0.570g)으로 혼합하였고, 상기 혼합물을 메탄올/디에틸에테르로부터 결정화하여 밝은 황색 결정으로서 푸마르산 염(44)을 얻었다(0.694g, 융점 178 내지 179℃).4- (t-butyloxycarbonylamino) hepta-1,6-diyne (43) (30.28 g, 0.146 mol) was cooled in ice and trifluoroacetic acid (90 ml) was added with stirring. The mixture was stirred for 20 minutes and excess trifluoroacetic acid was removed under vacuum. The mixture was partitioned between water and diethyl ether and the ether solution was extracted twice with 5% hydrochloric acid solution. The combined aqueous extracts were washed with ice-cold diethyl ether and basified with solid sodium hydroxide. The mixture was saturated with sodium chloride and extracted three times with diethyl ether. The combined extracts were brine and dried (MgSO 4 ). The solvent was removed in vacuo to yield the title compound (44) as amber oil (13.2 g, 84%). A sample (0.526 g) was mixed with fumaric acid (0.570 g), and the mixture was crystallized from methanol / diethyl ether to give fumaric acid salt 44 as light yellow crystals (0.694 g, melting point 178 to 179 ° C).

절차 30Procedure 30

4-(트리플루오로아세틸아미노)헵타-1,6-디인(45)4- (trifluoroacetylamino) hepta-1,6-diyne (45)

건조 테트라하이드로푸란(100ml)중의 4-아미노헵타-1,6-디인(44)(14.63g, 0.137mol) 및 트리에틸아민(20.8g, 0.206mol)의 용액을 얼음에서 냉각하였고, 트리플루오로아세트산 무수물(37.5g, 0.178mol)을 30분동안 수동펌프를 통해 가했다. 상기 혼합물을 0℃에서 1시간동안 교반하였고, -15℃에서 밤새 유지하였다. 상기 혼합물을 얼음에서 냉각하였고, 물(100ml)을 적가했다. 상기 혼합물을 디에틸에테르로 2회 추출하였다. 혼합된 유기 추출물을 10% 염산, 포화 중탄산나트륨 용액(2회) 및 염수로 세척하였다. 상기 용액을 건조(MgSO4)시켰고, 용매를 진공하에서 제거하여 고형물(29.6g)을 얻었다. 소량의 에틸 아세테이트를 함유하는 헥산으로부터 결정화하여 약간 황색 결정으로서 45를 얻었다(21.5g, 융점 55 내지 57℃).A solution of 4-aminohepta-1,6-diyne (44) (14.63 g, 0.137 mol) and triethylamine (20.8 g, 0.206 mol) in dry tetrahydrofuran (100 ml) was cooled on ice and trifluoro Acetic anhydride (37.5 g, 0.178 mol) was added via manual pump for 30 minutes. The mixture was stirred at 0 ° C. for 1 hour and kept at −15 ° C. overnight. The mixture was cooled on ice and water (100 ml) was added dropwise. The mixture was extracted twice with diethyl ether. The combined organic extracts were washed with 10% hydrochloric acid, saturated sodium bicarbonate solution (twice) and brine. The solution was dried (MgSO 4 ) and the solvent removed under vacuum to give a solid (29.6 g). Crystallization from hexane containing a small amount of ethyl acetate gave 45 as slightly yellow crystals (21.5 g, melting point 55-57 ° C).

절차 31Procedure 31

2-(트리플루오로아세틸아미노)-5,6-비스(아세톡시메틸)인단(47)2- (trifluoroacetylamino) -5,6-bis (acetoxymethyl) indane (47)

아르곤 탈기체화 에탄올(100ml)중의 2-부틴-1,4-디아세테이트(46)(34.03g, 0.200mol) 및 트리스(트리페닐포스핀)로듐 클로라이드(2.78g, 3.00mmol, 3mol%)의 용액을 80℃로 가열하고, 아르곤 탈기체화 에탄올(70ml)중의 4-(트리플루오로아세틸아미노)헵타-1,6-디인(20.32g, 0.100mol)의 용액을 2.5시간동안 수동펌프를 통해 가했다. 상기 혼합물을 8시간동안 75 내지 80℃에서 교반하였고, 실온에서 10시간동안 교반하였다. 용매를 진공하에서 제거하여 짙은 기름을 얻었다. 플래쉬 크로마토그래피로 정제(230 내지 400메쉬 실리카겔, 25 내지 30% 에틸 아세테이트/헥산)하여 호박색 고형물(24.5g)를 얻었다. 에틸 아세테이트/헥산으로부터 결정화는 황갈색 결정으로서 표제 화합물(47)을 얻었다(22.0g, 59%, 융점 98 내지 100℃).A solution of 2-butyne-1,4-diacetate 46 (34.03 g, 0.200 mol) and tris (triphenylphosphine) rhodium chloride (2.78 g, 3.00 mmol, 3 mol%) in argon degassed ethanol (100 ml) Was heated to 80 ° C. and a solution of 4- (trifluoroacetylamino) hepta-1,6-diyne (20.32 g, 0.100 mol) in argon degassed ethanol (70 ml) was added via manual pump for 2.5 hours. The mixture was stirred for 8 h at 75-80 ° C. and for 10 h at room temperature. The solvent was removed in vacuo to give a dark oil. Purification by flash chromatography (230-400 mesh silica gel, 25-30% ethyl acetate / hexanes) afforded an amber solid (24.5 g). Crystallization from ethyl acetate / hexanes gave the title compound (47) as tan crystals (22.0 g, 59%, melting point 98-100 ° C.).

절차 32 및 33Procedures 32 and 33

2-(N,N-디프로필아미노)-5,6-비스(하이드록시메틸)인단(49)2- (N, N-dipropylamino) -5,6-bis (hydroxymethyl) indane (49)

물(35ml)중의 수산화칼륨 용액(10.10g, 0.180mol)을 메탄올(200ml)중의 2-(트리플루오로아세틸아미노)-5,6-비스(아세톡시메틸)인단(47) 용액(20.1g, 53.8mmol)에 실온에서 가했고, 상기 혼합물을 2.5시간동안 환류로 가열하였다. 용매를 진공하에서 제거하여 2-아미노-5,6-비스(하이드록시메틸)인단(48)을 반고형물로서 얻었다. 조생성물을 아세토니트릴(100ml)중의 1-브로모프로판(27.1g, 0.220mol) 및 탄산칼륨(22.32g, 0.162mol)로 혼합하였다. 1-브로모프로판(6.8g, 0.055mol)을 가했고, 4시간동안 환류를 계속하였다. 혼합물을 물로 희석하였고, 에틸 아세테이트로 2회 추출하였다. 추출물을 염수로 세척하였고, 건조하였다(MgSO4). 용매를 진공하에서 제거하여 갈색 기름을 얻었다(15.75g). 플래쉬 크로마토그래피로 정제(230 내지 400메쉬 실리카 겔, 에틸 아세테이트중의 에틸 아세테이트 대 30% 테트라하이드로푸란)을 고형물(12.1g, 81%)로서 표제 화합물(49)을 얻었다. 시료(0.50g)를 에틸 아세테이트/헥산으로부터 결정화하여 백색 결정(0.48g)을 얻었다.A solution of potassium hydroxide (10.10 g, 0.180 mol) in water (35 ml) in 2- (trifluoroacetylamino) -5,6-bis (acetoxymethyl) indane (47) solution in methanol (200 ml) (20.1 g, 53.8 mmol) at room temperature and the mixture was heated to reflux for 2.5 h. The solvent was removed in vacuo to afford 2-amino-5,6-bis (hydroxymethyl) indane (48) as a semisolid. The crude product was mixed with 1-bromopropane (27.1 g, 0.220 mol) and potassium carbonate (22.32 g, 0.162 mol) in acetonitrile (100 ml). 1-bromopropane (6.8 g, 0.055 mol) was added and refluxing continued for 4 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The extract was washed with brine and dried (MgSO 4 ). The solvent was removed under vacuum to give a brown oil (15.75 g). Purification by flash chromatography (230-400 mesh silica gel, ethyl acetate in ethyl acetate versus 30% tetrahydrofuran) gave the title compound (49) as a solid (12.1 g, 81%). Sample (0.50 g) was crystallized from ethyl acetate / hexanes to give white crystals (0.48 g).

절차 34Procedure 34

2-(N,N-디프로필아미노)-5,6-비스(클로로메틸)인단(50)2- (N, N-dipropylamino) -5,6-bis (chloromethyl) indane (50)

2-(N,N-디프로필아미노)-5,6-비스(하이드록시메틸)인단(49)(2.78g, 10.0mmol)을 얼음에서 냉각하였고, 티오닐 클로라이드(8.0ml)를 천천히 가했다. 상기 혼합물을 1.25시간동안 증기욕에서 환류로 가열하였다. 과량의 티오닐 클로라이드를 진공하에서 제거하였다. 잔사를 클로로포름중에서 용해하였고, 용매를 진공하에서 제거하였다. 이것을 호박색 고형물을 얻도록 반복하였다. 모든 고형물이 용해될때까지 10% 탄산나트륨 및 테트라하이드로푸란의 혼합물로 화합물을 교반하였다. 상기 혼합물을 디에틸에테르로 2회 추출하였고, 혼합 추출물을 염수로 세척하였고, 건조하였다(MgSO4). 용매를 진공하에서 제거하여 기름(3.46g)으로서 표제 화합물(50)을 얻었다.2- (N, N-dipropylamino) -5,6-bis (hydroxymethyl) indane 49 (2.78 g, 10.0 mmol) was cooled on ice and thionyl chloride (8.0 ml) was added slowly. The mixture was heated to reflux in a steam bath for 1.25 h. Excess thionyl chloride was removed under vacuum. The residue was dissolved in chloroform and the solvent was removed in vacuo. This was repeated to obtain an amber solid. The compound was stirred with a mixture of 10% sodium carbonate and tetrahydrofuran until all solids dissolved. The mixture was extracted twice with diethyl ether and the combined extracts were washed with brine and dried (MgSO 4 ). The solvent was removed in vacuo to afford the title compound (50) as oil (3.46 g).

절차 35 및 36Procedure 35 and 36

2-(N,N-디프로필아미노)-5,6-비스(아미노메틸)인단(52)2- (N, N-dipropylamino) -5,6-bis (aminomethyl) indane (52)

실온에서 디메틸포름아미드(35ml)중의 2-(N,N-디프로필아미노)-5,6-비스(클로로메틸)인단(50)(2.85g, 9.07mmol)의 용액에 소디움 아지드(3.30g, 50.8mmol)를 가했고, 상기 혼합물을 80℃에서 밤새 교반하였다. 상기 혼합물을 물로 희석하였고, 메틸-t-부틸에테르로 3회 추출하였다. 혼합 추출물을 물로 2회 및 염수로 1회 세척하였다. 용액을 건조하였고(MgSO4), 여과하였다. 2-(N,N-디프로필아미노)-5,6-비스(이지도메틸)인단(51)을 함유하는 용액을 얼음에서 냉각하였고, 리튬 알루미늄 하이드라이드(테트라하이드로푸란중의 1.0M, 13ml, 13mmol)를 천천히 가했고, 생성된 반응물을 실온에서 2시간동안 교반하였다. 물(0.5ml), 15% 수산화나트륨(0.5ml) 및 물(1.5ml)을 연속적으로 가했다. 혼합물을 30분동안 교반하였고, 여과하였다. 알루미늄 염을 테트라하이드로푸란으로 세척하였고, 혼합 여과물을 증발시켜 호박색 기름(2.27g)을 얻었다. 화합물을 메탄올(100ml)중에서 용해하였고, 마그네슘 금속(2.5g)을 가했다. 반응물이 발열성이 될때까지 혼합물을 증기욕에서 가열하였다. 마그네슘이 감소되었고, 용매를 진공하에서 제거하여 고형물을 얻었다. 혼합물을 물에 현탁하였고, 1:1 테트라하이드로푸란/디에틸에테르(유제)로 수회 추출하였다. 혼합 추출물을 염수로 세척하였고, 건조하였다(MgSO4). 용매를 진공하에서 제거하여 갈색 기름(0.92g)으로서 표제 화합물을 얻었다.Sodium azide (3.30 g) in a solution of 2- (N, N-dipropylamino) -5,6-bis (chloromethyl) indane 50 (2.85 g, 9.07 mmol) in dimethylformamide (35 ml) at room temperature. , 50.8 mmol) was added and the mixture was stirred at 80 ° C overnight. The mixture was diluted with water and extracted three times with methyl-t-butylether. The combined extracts were washed twice with water and once with brine. The solution was dried (MgSO 4 ) and filtered. The solution containing 2- (N, N-dipropylamino) -5,6-bis (izidomethyl) indane 51 was cooled in ice and lithium aluminum hydride (1.0 M in tetrahydrofuran, 13 ml , 13 mmol) was slowly added and the resulting reaction was stirred at room temperature for 2 hours. Water (0.5 ml), 15% sodium hydroxide (0.5 ml) and water (1.5 ml) were added successively. The mixture was stirred for 30 minutes and filtered. The aluminum salt was washed with tetrahydrofuran and the mixed filtrate was evaporated to give amber oil (2.27 g). The compound was dissolved in methanol (100 ml) and magnesium metal (2.5 g) was added. The mixture was heated in a steam bath until the reaction became exothermic. Magnesium was reduced and the solvent was removed in vacuo to give a solid. The mixture was suspended in water and extracted several times with 1: 1 tetrahydrofuran / diethyl ether (emulsion). The combined extracts were washed with brine and dried (MgSO 4 ). The solvent was removed in vacuo to yield the title compound as brown oil (0.92 g).

절차 37Procedure 37

2-(N,N-디프로필아미노)-5,6-비스(4-클로로페닐설포닐아미노메틸)인단(53)2- (N, N-dipropylamino) -5,6-bis (4-chlorophenylsulfonylaminomethyl) indane (53)

피리딘(4.0ml)중에 2-(N,N-디프로필아미노)-5,6-비스(아미노메틸)인단(52)(0.276g, 1.00mmol)의 용액을 얼음에서 냉각하였고, 4-클로로벤젠설포닐 클로라이드(0.53g, 2.51mmol)을 가했다. 혼합물을 0℃에서 40분동안 교반하였고, 실온에서 18시간 교반하였다. 물을 가했고, 상기 혼합물을 실온에서 1시간동안 교반하였다. 혼합물을 10% 탄산나트륨 용액으로 희석하였고, 디에틸에테르로 2회 및 에틸 아세테이트로 1회 추출하였다. 혼합 추출물을 염수로 세척하였고, 건조하였다(MgSO4). 용매를 진공하에서 제거하여 적갈색 기름(0.34g)을 얻었다. 플래쉬 크로마토그래피로 정제(230 내지 400 메쉬 실리카겔, 60% 에틸 아세테이트/헥산)하여 오랜지색 고형물을 얻었다. 디에틸에테르/헥산으로부터 결정화하여 약간 오랜지색 결정으로서 표제 화합물(53)을 얻었다(0.090g, 융점 140 내지 141℃).A solution of 2- (N, N-dipropylamino) -5,6-bis (aminomethyl) indane 52 (0.276 g, 1.00 mmol) in pyridine (4.0 ml) was cooled on ice and 4-chlorobenzene Sulfonyl chloride (0.53 g, 2.51 mmol) was added. The mixture was stirred at 0 ° C. for 40 minutes and at room temperature for 18 hours. Water was added and the mixture was stirred at rt for 1 h. The mixture was diluted with 10% sodium carbonate solution and extracted twice with diethyl ether and once with ethyl acetate. The combined extracts were washed with brine and dried (MgSO 4 ). The solvent was removed in vacuo to give reddish brown oil (0.34 g). Purification by flash chromatography (230-400 mesh silica gel, 60% ethyl acetate / hexanes) gave an orange solid. Crystallization from diethyl ether / hexane gave the title compound (53) as slightly orange crystals (0.090 g, melting point 140 to 141 ° C).

절차 38Procedure 38

2-(N,N-디프로필아미노)-5,6-비스(4-시아노페닐설포닐아미노메틸)인단(54)2- (N, N-dipropylamino) -5,6-bis (4-cyanophenylsulfonylaminomethyl) indane (54)

피리딘(4.0ml)중에 2-(N,N-디프로필아미노)-5,6-비스(아미노메틸)인단(52)(0.276g, 1.00mmol)의 용액을 얼음에서 냉각하였고, 4-시아노벤젠설포닐 클로라이드(0.61g, 3.0mmol)을 가했다. 혼합물을 실온에서 4시간동안 교반하였다. 혼합물을 10% 탄산나트륨 용액으로 희석하였고, 에틸 아세테이트로 3회 추출하였다. 혼합 추출물을 염수로 세척하였고, 건조하였다(MgSO4). 용매를 진공하에서 제거하여 짙은 기름을 얻었다. 플래쉬 크로마토그래피로 정제(230 내지 400 메쉬 실리카겔, 60 내지 80% 에틸 아세테이트/헥산)하여 기름으로서 표제 화합물(54)을 얻었다. 상기 화합물을 에틸 아세테이트중에서 용해하였고, 과량의 에테르성 염산을 가했다. 혼합물을 디에틸에테르로 희석하였고, 여과하였다. 침전물을 디에틸에테르로 세척하였고, 진공하에서 건조하여 황갈색 고형물(0.143g)로서 화합물(54)의 염산염을 얻었다.A solution of 2- (N, N-dipropylamino) -5,6-bis (aminomethyl) indane 52 (0.276 g, 1.00 mmol) in pyridine (4.0 ml) was cooled on ice and 4-cyano Benzenesulfonyl chloride (0.61 g, 3.0 mmol) was added. The mixture was stirred at rt for 4 h. The mixture was diluted with 10% sodium carbonate solution and extracted three times with ethyl acetate. The combined extracts were washed with brine and dried (MgSO 4 ). The solvent was removed in vacuo to give a dark oil. Purification by flash chromatography (230-400 mesh silica gel, 60-80% ethyl acetate / hexanes) gave the title compound (54) as an oil. The compound was dissolved in ethyl acetate and excess ether hydrochloric acid was added. The mixture was diluted with diethyl ether and filtered. The precipitate was washed with diethyl ether and dried under vacuum to give the hydrochloride of compound (54) as a tan solid (0.143 g).

절차 39Procedure 39

2-(N,N-디프로필아미노)-5,6-비스(S-프로필설포닐아미노메틸)인단(55)2- (N, N-dipropylamino) -5,6-bis (S-propylsulfonylaminomethyl) indane (55)

피리딘(5.0ml)중에 2-(N,N-디프로필아미노)-5,6-비스(아미노메틸)인단(52)(0.36g, 1.3mmol)의 용액을 얼음에서 냉각하였고, 1-프로판설포닐 클로라이드(0.64g, 4.5mmol)을 가했다. 혼합물을 0℃에서 30분동안 및 실온에서 3시간동안 교반하였다. 물(15ml)을 가했고, 상기 혼합물을 실온에서 15분동안 교반하였다. 혼합물을 10% 탄산나트륨 용액으로 희석하였고, 디에틸에테르로 3회 추출하였다. 혼합 추출물을 염수로 세척하였고, 건조하였다(MgSO4). 용매를 진공하에서 제거하여 갈색 기름(0.51g)을 얻었다. 플래쉬 크로마토그래피로 정제(230 내지 400 메쉬 실리카겔, 80% 에틸 아세테이트/헥산)하여 황색 기름(0.131g)을 얻었다. 디에틸에테르/헥산으로부터 결정화는 탈백색 결정으로 표제 화합물(55)을 얻었다(0.092g, 융점 120 내지 121℃).A solution of 2- (N, N-dipropylamino) -5,6-bis (aminomethyl) indane 52 (0.36 g, 1.3 mmol) in pyridine (5.0 ml) was cooled on ice and 1-propanesul Ponyl chloride (0.64 g, 4.5 mmol) was added. The mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 3 hours. Water (15 ml) was added and the mixture was stirred at rt for 15 min. The mixture was diluted with 10% sodium carbonate solution and extracted three times with diethyl ether. The combined extracts were washed with brine and dried (MgSO 4 ). The solvent was removed in vacuo to give brown oil (0.51 g). Purification by flash chromatography (230-400 mesh silica gel, 80% ethyl acetate / hexanes) gave yellow oil (0.131 g). Crystallization from diethyl ether / hexane gave the title compound (55) as dewhite crystals (0.092 g, melting point: 120-121 ° C).

절차 40Procedure 40

2-(N,N-디프로필아미노)-5,6-비스(페닐설포닐메틸)인단(56)2- (N, N-dipropylamino) -5,6-bis (phenylsulfonylmethyl) indane (56)

100℃에서 디메틸포름아미드중의 2-(N,N-디프로필아미노)-5,6-비스(클로로메틸)인단 및 소디움 벤젠설피네이트로부터 표제 화합물(56)을 제조하였다. 유리염기는 푸마르산에 의해 푸마르산 염으로 전환되었다(융점 160 내지 168℃).The title compound (56) was prepared from 2- (N, N-dipropylamino) -5,6-bis (chloromethyl) indane and sodium benzenesulfinate at 100 ° C. in dimethylformamide. The free base was converted to fumaric acid salt by fumaric acid (melting point 160-168 ° C.).

Claims (9)

화학식 (I)의 화합물 또는 그의 약학적으로 허용가능한 염:Compound of Formula (I) or a pharmaceutically acceptable salt thereof: 화학식 IFormula I 상기 식에서,Where R1및 R2는 독립적으로 H, C1-C8알킬 또는 C1-C18알킬아릴이고;R 1 and R 2 are independently H, C 1 -C 8 alkyl or C 1 -C 18 alkylaryl; X는 CH2R3또는 NHSO2R4이고;X is CH 2 R 3 or NHSO 2 R 4 ; Y는 수소, CH2R3, NHSO2R4, CONR1R2, SO2NR1R2, SO2CH3, 할로겐, OSO2CF3, SCH3또는 OCH3이고;Y is hydrogen, CH 2 R 3 , NHSO 2 R 4 , CONR 1 R 2 , SO 2 NR 1 R 2 , SO 2 CH 3 , halogen, OSO 2 CF 3 , SCH 3 or OCH 3 ; R3는 NHSO2R4, SO2R4, CONR1R2또는 아릴이고; 및R 3 is NHSO 2 R 4 , SO 2 R 4 , CONR 1 R 2 or aryl; And R4는 NR1R2, C1-C8알킬, 아릴 또는 C1-C8알킬아릴이다.R 4 is NR 1 R 2 , C 1 -C 8 alkyl, aryl or C 1 -C 8 alkylaryl. 제 1 항에 있어서,The method of claim 1, Y가 CONR1R2, SO2NR1R2또는 SO2CH3인 화합물.Y is CONR 1 R 2 , SO 2 NR 1 R 2 or SO 2 CH 3 . 제 2 항에 있어서,The method of claim 2, R1및 R2가 독립적으로 H 또는 C1-C8알킬인 화합물.R 1 and R 2 are independently H or C 1 -C 8 alkyl. 제 1 항에 있어서,The method of claim 1, R1및 R2가 독립적으로 H 또는 C1-C8알킬인 화합물.R 1 and R 2 are independently H or C 1 -C 8 alkyl. 제 1 항에 있어서,The method of claim 1, R4가 C1-C8알킬인 화합물.R 4 is C 1 -C 8 alkyl. 제 1 항에 있어서,The method of claim 1, R3가 CONR1R2이고, R1및 R2가 독립적으로 H 또는 C1-C8알킬인 화합물.R 3 is CONR 1 R 2 , and R 1 and R 2 are independently H or C 1 -C 8 alkyl. 치료학적으로 유효량의 제 1 항의 화합물을 그의 필요한 환자에게 투여하는 것을 포함하는 도파민 D3 수용체 활성과 관련된 중추 신경계 질환의 치료에 유용한 약제의 제조를 위한 제 1 항의 화합물의 용도.Use of a compound of claim 1 for the manufacture of a medicament useful for the treatment of central nervous system diseases associated with dopamine D3 receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1. 제 7 항에 있어서,The method of claim 7, wherein 상기 화합물이 정신분열증, 조병, 우울증, 노인성 질환, 약물 남용 및 약물 중독, 파킨슨병, 수면 질환, 일주기 질환, 불안 질환 및 치매로부터 고통받는 환자에게 투여되는 용도.The compound is administered to a patient suffering from schizophrenia, manic, depression, senile disease, drug abuse and drug addiction, Parkinson's disease, sleep disease, circadian disease, anxiety disease and dementia. 제 7 항에 있어서,The method of claim 7, wherein 상기 화합물이 개인당 약 0.25mg 내지 약 100mg의 양으로 투여되는 용도.The compound is administered in an amount of about 0.25 mg to about 100 mg per person.
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